Substituted cyclyl-acetic acid derivatives for the treatment of metabolic disorders

ABSTRACT

Provided is a novel aromatic ring compound which may have a GPR40 agonist activity and a GLP-1 secretagogue action. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof may have a GPR40 agonist activity and a GLP-1 secretagogue action, may be useful for the prophylaxis or treatment of cancer, obesity, diabetes, hypertension, hyperlipidemia, cardiac failure, diabetic complications, metabolic syndrome, sarcopenia and the like, and may afford superior efficacy.

TECHNICAL FIELD

The present invention relates to a novel aromatic ring compound whichmay have a GPR40 agonist activity and GLP-1 secretagogue action.

BACKGROUND OF THE INVENTION

Patent document 1 describes the following compound.

wherein each symbol is as described in patent document 1.

Patent document 2 describes the following compound.

wherein each symbol is as described in patent document 2.

Patent document 3 describes the following compound.

wherein each symbol is as described in patent document 3.

Patent document 4 describes the following compound.

wherein each symbol is as described in patent document 4.

Patent document 5 describes the following compound.

wherein each symbol is as described in patent document 5.

Patent document 6 describes the following compound.

wherein each symbol is as described in patent document 6.

Patent document 7 describes the following compound.

wherein each symbol is as described in patent document 7.

However, no documents specifically disclose the compound of the presentapplication.

DOCUMENT LIST Patent Documents

patent document 1: WO2009/048527patent document 2: US2009-0012093patent document 3: US2006-0258722patent document 4: US2007-0149608patent document 5: US2010-0144806patent document 6: WO2013/122029patent document 7: WO2015/020184

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a novel aromatic ring compoundwhich may have a GPR40 agonist activity and GLP-1 secretagogue action,and expected to be useful as an agent for the prophylaxis or treatmentof diabetes and the like.

Means of Solving the Problems

The present inventors have intensively conducted various studies andfound that a compound represented by the formula (I) may unexpectedlyhave a superior GPR40 agonist activity and a GLP-1 secretagogue action,and may provide a safe and useful medicament as an agent for theprophylaxis or treatment of a GPR40 receptor-related pathology ordisease in mammals. They have completed the present invention based onthese findings.

That is, the present invention relates to

[1] a compound represented by the formula (I):

wherein X is an oxygen atom or a bond;Y¹ and Y² are each independently CH or N;Z is an optionally substituted alkyl group, an optionally substitutedalkoxy group or a halogen atom;W is an optionally substituted alkyl group, an optionally substitutedalkoxy group, —NR^(W1)R^(W2), an optionally substituted carbamoyl groupor an optionally substituted cyclic group;R^(W1) is an optionally substituted alkyl group or an acyl group;R^(W2) is a hydrogen atom or a substituent;

L is

andR¹, R² and R³ are each independently a hydrogen atom or a substituent;orR¹ and R² are optionally bonded to each other to form, together witheach adjacent carbon atom, an optionally further substituted 3- to6-membered ring,or a salt thereof (hereinafter sometimes to be referred to as compound(I));[2] the compound of the above-mentioned [1], wherein

Z is a C₁₋₆ alkoxy group;

W is

(1) a C₁₋₁₀ alkyl group optionally substituted by 1 to 5 halogen atoms,(2) a C₁₋₁₀ alkoxy group optionally substituted by 1 to 5 halogen atoms,(3) a C₆₋₁₄ aryl group optionally substituted by 1 to 5 substituentsselected from

(a) a C₁₋₆ alkoxy group optionally substituted by 1 to 5 halogen atoms,and

(b) a 3- to 14-membered non-aromatic heterocyclic group,

(4) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 5 substituents selected from

(a) a C₁₋₆ alkyl group optionally substituted by 1 to 5 halogen atoms,and

(b) a C₁₋₆ alkoxy group optionally substituted by 1 to 5 halogen atoms,

(5) a 3- to 14-membered non-aromatic heterocyclic group optionallysubstituted by 1 to 5 substituents selected from C₁₋₆ alkyl groupsoptionally substituted by 1 to 5 halogen atoms,(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group, and

(b) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 5 C₁₋₆ alkyl groups, or

(7) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 5 halogenatoms;

R¹ is a hydrogen atom or a C₁₋₆ alkyl group, and R² and R³ are each ahydrogen atom;

or a salt thereof;[3] the compound of the above-mentioned [1], wherein

X is an oxygen atom or a bond;

Y¹ is CH or N;

Y² is N;

Z is a C₁₋₆ alkoxy group;

W is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 5 halogen atoms,(2) a C₁₋₆ alkoxy group optionally substituted by 1 to 5 halogen atoms,(3) a 3- to 14-membered non-aromatic heterocyclic group optionallysubstituted by 1 to 5 substituents selected from C₁₋₆ alkyl groupsoptionally substituted by 1 to 5 halogen atoms, or(4) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 5 halogenatoms;

L is

and

R¹, R² and R³ are each a hydrogen atom;

or a salt thereof;[4](6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof;[5](6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof;[6](6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof;[7](6-((1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof;[8](6-((1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof;[9] a medicament comprising the compound of the above-mentioned [1] or asalt thereof;[10] the medicament of the above-mentioned [9], which is a GPR40receptor function regulator;[11] the medicament of the above-mentioned [9], which is a prophylacticor therapeutic agent for diabetes;[12] a method for regulating GPR40 receptor function in a mammal,comprising administering an effective amount of the compound of theabove-mentioned [1] or a salt thereof to the mammal;[13] a method for preventing or treating obesity or diabetes in amammal, comprising administering an effective amount of the compound ofthe above-mentioned [1] or a salt thereof to the mammal;[14] use of the compound of the above-mentioned [1] or a salt thereoffor the production of an agent for the prophylaxis or treatment ofobesity or diabetes;[15] the compound of the above-mentioned [1] or a salt thereof for usefor the prophylaxis or treatment of obesity or diabetes;and the like.

Effect of the Invention

Since compound (I) may have a superior GPR40 agonist activity and GLP-1secretagogue action, may be superior in the property as a pharmaceuticalproduct such as stability and the like, and may particularly show highsolubility, low toxicity, good kinetics such as sustainability in bloodand the like, it can provide a safe and useful agent for the prophylaxisor treatment of mammalian GPR40 receptor-related pathology or disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail in the following.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenated C₁alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[substituent group A](1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a (C₁₋₆alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane, and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene, and cyclooctene.

In the present specification, examples of the “heterocycle” includearomatic heterocycle and non-aromatic heterocycle, each containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic(preferably bi- or tricyclic) aromatic heterocycles such asbenzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,benzothiazole, benzisothiazole, benzotriazole, imidazopyridine,thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine,thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine,pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiine, indole,isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, phenothiazine,phenoxathiine and the like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepane, diazepane, azepine, azocane, diazocane, oxepane and the like;and

9- to 14-membered fused polycyclic the formula (preferably 2- ortricyclic) non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzoimidazole, dihydrobenzooxazole, dihydrobenzothiazole,dihydrobenzoisothiazole, dihydronaphto[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include a “heterocycle” containing at least one nitrogenatom as a ring constituting atom.

In the present specification, examples of the “aromatic ring” (including“aromatic ring” in the “optionally further substituted aromatic ring”)include a C₆₋₁₄ aromatic hydrocarbon ring, and aromatic heterocycle.

In the present specification, the “aromatic ring” of the “optionallyfurther substituted aromatic ring” optionally has 1 to 5, preferably 1to 3, substituents at substitutable position(s). When the number of thesubstituents is not less than 2, the respective substituents may be thesame or different.

In the present specification, examples of the “optionally substitutedC₁₋₆ alkyl group” include the “optionally substituted hydrocarbon group”wherein the hydrocarbon group is a “C₁₋₆ alkyl group”.

In the present specification, examples of the “optionally substitutedC₃₋₁₀ cycloalkyl group” include the “optionally substituted hydrocarbongroup” wherein the hydrocarbon group is a “C₃₋₁₀ cycloalkyl group”.

In the present specification, the “C₁₋₆ alkoxy group” of the “optionallysubstituted C₁₋₆ alkoxy group” optionally has 1 to 5, preferably 1 to 3,substituents, at substitutable position(s). When the number of thesubstituents is not less than 2, the respective substituents may be thesame or different.

In the present specification, examples of the “4-6-memberednitrogen-containing saturated ring” (including the “4-6-memberednitrogen-containing saturated ring” of the “optionally furthersubstituted 4-6-membered nitrogen-containing saturated ring”) includethe above-mentioned “nitrogen-containing heterocycle” which is 4- to6-membered and saturated.

In the present specification, the “4-6-membered nitrogen-containingsaturated ring” of the “optionally further substituted 4- to 6-memberednitrogen-containing saturated ring” preferably optionally has 1 to 5,preferably 1 to 3 substituents at substitutable position(s). When thenumber of the substituents is not less than 2, the respectivesubstituents may be the same or different.

In the present specification, examples of the “3- to 10-membered ring”(including the “3- to 10-membered ring” of the “optionally substituted3- to 10-membered ring”) include the above-mentioned “hydrocarbon ring”and “heterocycle” which are 3- to 10-membered.

In the present specification, the “3- to 10-membered ring” of the“optionally substituted 3- to 10-membered ring” optionally has 1 to 5,preferably 1 to 3, substituents, at substitutable position(s). When thenumber of the substituents is not less than 2, the respectivesubstituents may be the same or different.

In the present specification, examples of the “C₁₋₁₀ alkyl group”include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl, 4,4-dimethylpentyl, 5,5-dimethylhexyl and6,6-dimethylheptyl.

In the present specification, examples of the “C₁₋₁₀ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, isohexyloxy,1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy,2-ethylbutoxy, 4,4-dimethylpentyloxy, 5,5-dimethylhexyloxy and6,6-dimethylheptyloxy.

The definition of each symbol in the formula (I) is described in detailin the following.

X is an oxygen atom or a bond.

Y¹ is CH or N.

Y² is CH or N. Y² is preferably N.

Z is an optionally substituted alkyl group, an optionally substitutedalkoxy group or a halogen atom.

Examples of the substituent of the “optionally substituted alkyl group”and “optionally substituted alkoxy group” for Z include substituentsselected from the “substituent” defined above. The number of theabove-mentioned substituents in each of the “optionally substitutedalkyl group” and “optionally substituted alkoxy group” is, for example,1 to 5, preferably 1 to 3. When the number of the substituents is two ormore, the respective substituents may be the same or different.

Examples of the “alkyl group” of the “optionally substituted alkylgroup” for Z include a C₁₋₆ alkyl group. Examples of the “alkoxy group”of the “optionally substituted alkoxy group” for Z include a C₁₋₆ alkoxygroup.

Z is preferably a C₁₋₆ alkoxy group (e.g., methoxy) or a halogen atom,more preferably a C₁₋₆ alkoxy group (e.g., methoxy).

In another embodiment of the present invention, Z is preferably a C₁₋₆alkyl group (e.g., methyl, ethyl), a C₁₋₆ alkoxy group (e.g., methoxy)or a halogen atom (e.g., chlorine atom), more preferably a C₁₋₆ alkoxygroup (e.g., methoxy).

W is an optionally substituted alkyl group, an optionally substitutedalkoxy group, —NR^(W1)R^(W2), an optionally substituted carbamoyl groupor an optionally substituted cyclic group. R^(W1) is an optionallysubstituted alkyl group or an acyl group. R^(W2) is a hydrogen atom or asubstituent.

Examples of the substituent of the “optionally substituted alkyl group”,“optionally substituted alkoxy group”, “optionally substituted carbamoylgroup” and “optionally substituted cyclic group” for W includesubstituents selected from the “substituent” defined above. The numberof the above-mentioned substituents in each of the “optionallysubstituted alkyl group”, “optionally substituted alkoxy group”,“optionally substituted carbamoyl group” and “optionally substitutedcyclic group” is, for example, 1 to 5, preferably 1 to 3. When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

Examples of the “alkyl group” of the “optionally substituted alkylgroup” for W include a C₁₋₁₀ alkyl group. Examples of the “alkoxy group”of the “optionally substituted alkoxy group” for W include a C₁₋₁₀alkoxy group.

Examples of the “cyclic group” of the “optionally substituted cyclicgroup” for W include a C₆₋₁₄ aryl group, a C₃₋₁₀ cycloalkyl group, aC₃₋₁₀ cycloalkenyl group, a 5- to 14-membered aromatic heterocyclicgroup, a 3- to 14-membered non-aromatic heterocyclic group and the like.

Examples of the substituent of the “optionally substituted alkyl group”for R^(W1) include substituents selected from the “substituent” definedabove. The number of the substituents in the “optionally substitutedalkyl group” is, for example, 1 to 5, preferably 1 to 3. When the numberof the substituents is two or more, the respective substituents may bethe same or different.

Examples of the “alkyl group” of the “optionally substituted alkylgroup” for R^(W1) include a C₁₋₆ alkyl group.

W is preferably

(1) a C₁₋₁₀ alkyl group (e.g., propyl, isopropyl, butyl,4,4-dimethylpentyl) optionally substituted by 1 to 5 halogen atoms(e.g., fluorine atom),(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom),(3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 5substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,morpholinyl),

(4) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 substituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., ethoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),

(5) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl, propyl) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom), or(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group (e.g., neopentyl), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 C₁₋₆ alkyl groups (e.g.,methyl).

W is more preferably

(1) a C₁₋₁₀ alkyl group (e.g., propyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom) or(3) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom).

In another embodiment of the present invention, W is preferably

(1) a C₁₋₁₀ alkyl group (e.g., methyl, propyl, isopropyl, butyl,4,4-dimethylpentyl) optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,pyrrolidinyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine atom),

(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom),(3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 5substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,morpholinyl),

(4) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 substituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., ethoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),

(5) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl, tetrahydropyranyl) optionally substituted by 1 tosubstituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionallysubstituted by 1 to 5 halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group (e.g., neopentyl),

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 C₁₋₆ alkyl groups (e.g.,methyl), or

(7) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine atom).

In another embodiment of the present invention, W is more preferably

(1) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),(2) a C₁₋₆ alkoxy group (e.g., propoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),(3) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), or(4) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine atom).

L is

As used herein, * shows the binding site to a carbon atom of thearomatic ring and ** shows the binding site to O.

R¹, R² and R³ are each independently a hydrogen atom or a substituent.Alternatively, R¹ and R² are optionally bonded to each other to form,together with each adjacent carbon atom, an optionally furthersubstituted 3- to 6-membered ring.

Examples of the substituent of the “optionally further substituted 3- to6-membered ring” formed by R¹ and R² include substituents selected fromthe “substituent” defined above. The number of the substituents of the“optionally further substituted 3- to 6-membered ring” is, for example,1 to 5, preferably 1 to 3. When the number of the substituents is two ormore, the respective substituents may be the same or different.

Examples of the “3- to 6-membered ring” of the “optionally furthersubstituted 3- to 6-membered ring” formed by R¹ and R² include C₃₋₆cycloalkane (e.g., 3- to 6-membered ones among “C₃₋₁₀ cycloalkane”exemplified above), C₃₋₆ cycloalkene (e.g., 3- to 6-membered ones among“C₃₋₁₀ cycloalkene” exemplified above) and 3- to 6-membered monocyclicnon-aromatic heterocycle (e.g., 3- to 6-membered ones among “3- to8-membered monocyclic non-aromatic heterocycle” exemplified above).

Preferably, R¹, R² and R³ are each independently a hydrogen atom or aC₁₋₆ alkyl group (e.g., methyl). More preferably, R¹ is a hydrogen atomor a C₁₋₆ alkyl group (e.g., methyl), and R² and R³ are each a hydrogenatom. Further preferably, R¹, R² and R³ are each a hydrogen atom.

Preferable examples of compound (I) include the following compounds.

[Compound I-1]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ and Y² are each independently CH or N;

Z is a C₁₋₆ alkoxy group (e.g., methoxy);

W is

(1) a C₁₋₁₀ alkyl group (e.g., propyl, isopropyl, butyl,4,4-dimethylpentyl) optionally substituted by 1 to 5 halogen atoms(e.g., fluorine atom),(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom),(3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 5substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,morpholinyl),

(4) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 substituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., ethoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),

(5) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl, propyl) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom), or(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group (e.g., neopentyl), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 C₁₋₆ alkyl groups (e.g.,methyl);

L is

R¹ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl), and R² andR³ is a hydrogen atom.

[Compound I-2]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ is CH;

Y² is N;

Z is a C₁₋₆ alkoxy group (e.g., methoxy);

W is

(1) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrimidinyl)optionally substituted by 1 to 5 substituents selected from a C₁₋₆alkoxy group (e.g., ethoxy) optionally substituted by 1 to 5 halogenatoms (e.g., fluorine atom), or(2) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl, propyl) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom);

L is

and

R¹, R² and R³ are each a hydrogen atom.

[Compound I-3]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ and Y² are each independently CH or N;

Z is a C₁₋₆ alkoxy group (e.g., methoxy);

W is

(1) a C₁₋₁₀ alkyl group (e.g., propyl, isopropyl, butyl,4,4-dimethylpentyl) optionally substituted by 1 to 5 halogen atoms(e.g., fluorine atom),(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom),(3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 5substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,morpholinyl),

(4) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl)optionally substituted by 1 to 5 substituents selected from a C₁₋₆ alkylgroup (e.g., methyl) optionally substituted by 1 to 5 halogen atoms(e.g., fluorine atom),(5) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl, propyl) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom), or(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group (e.g., neopentyl), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 C₁₋₆ alkyl groups (e.g.,methyl);

L is

and

R¹ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl) and R² and R³are each a hydrogen atom.

[Compound I-4]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ is CH or N;

Y² is N;

Z is a C₁₋₆ alkoxy group (e.g., methoxy);

W is

(1) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),(2) a C₁₋₆ alkoxy group (e.g., propoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), or(3) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom);

L is

and

R¹, R² and R³ are each a hydrogen atom.

[Compound I-5]

Compounds (I) of Examples 1-48.

[Compound I-6]

Compound (I) selected from

-   (6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 1);-   (6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 2);-   (3-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (compound of Example 3);-   (3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (compound of Example 4);-   (6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 5);-   (6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 6);-   (6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 7);-   (6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 8);-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 9);-   (3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (Optical Isomer) (compound of Example 10);-   (6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (optical isomer) (compound of Example 11);-   (6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (optical isomer) (compound of Example 17);-   (6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 18);-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 28);-   (3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (Optical Isomer) (compound of Example 29); and-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 36).

[Compound I-7]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ and Y² are each independently CH or N;

Z is a C₁₋₆ alkyl group (e.g., methyl, ethyl), C₁₋₆ alkoxy group (e.g.,methoxy) or a halogen atom (e.g., chlorine atom);

W is

(1) a C₁₋₁₀ alkyl group (e.g., methyl, propyl, isopropyl, butyl,4,4-dimethylpentyl) optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,pyrrolidinyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine atom),

(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom),(3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 5substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,morpholinyl),

(4) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 substituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., ethoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),

(5) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl, tetrahydropyranyl) optionally substituted by 1 tosubstituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionallysubstituted by 1 to 5 halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group (e.g., neopentyl), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 C₁₋₆ alkyl groups (e.g.,methyl), or

(7) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine atom);

L is

and

R¹ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl), and R² andR³ are each a hydrogen atom.

[Compound I-8]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ and Y² are each independently CH or N;

Z is a C₁₋₆ alkyl group (e.g., methyl, ethyl), a C₁₋₆ alkoxy group(e.g., methoxy) or a halogen atom (e.g., chlorine atom);

W is

(1) a C₁₋₁₀ alkyl group (e.g., methyl, propyl, isopropyl, butyl,4,4-dimethylpentyl) optionally substituted by 1 to 5 substituentsselected from

(a) a halogen atom (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,pyrrolidinyl) optionally substituted by 1 to 5 halogen atoms (e.g.,fluorine atom),

(2) a C₁₋₁₀ alkoxy group (e.g., propoxy) optionally substituted by 1 to5 halogen atoms (e.g., fluorine atom),(3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to 5substituents selected from

(a) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), and

(b) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,morpholinyl),

(4) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl)optionally substituted by 1 to 5 substituents selected from a C₁₋₆ alkylgroup (e.g., methyl) optionally substituted by 1 to 5 halogen atoms(e.g., fluorine atom),(5) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl, tetrahydropyranyl) optionally substituted by 1 tosubstituents selected from

(a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionallysubstituted by 1 to 5 halogen atoms (e.g., fluorine atom), and

(b) a C₁₋₆ alkoxy group (e.g., methoxy),

(6) a carbamoyl group optionally mono- or di-substituted bysubstituent(s) selected from

(a) a C₁₋₆ alkyl group (e.g., neopentyl), and

(b) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl,pyrimidinyl) optionally substituted by 1 to 5 C₁₋₆ alkyl groups (e.g.,methyl), or

(7) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine atom);

L is

and

R¹ is a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl) and R² and R³are each a hydrogen atom.

[Compound I-9]

Compound (I) wherein

X is an oxygen atom or a bond;

Y¹ is CH or N;

Y² is N;

Z is a C₁₋₆ alkoxy group (e.g., methoxy);

W is

(1) a C₁₋₆ alkyl group (e.g., propyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),(2) a C₁₋₆ alkoxy group (e.g., propoxy) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom),(3) a 3- to 14-membered non-aromatic heterocyclic group (e.g.,piperidinyl) optionally substituted by 1 to 5 substituents selected froma C₁₋₆ alkyl group (e.g., ethyl) optionally substituted by 1 to 5halogen atoms (e.g., fluorine atom), or(4) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally substitutedby 1 to 5 halogen atoms (e.g., fluorine atom);

L is

and

R¹, R² and R³ are each a hydrogen atom.

[Compound I-10]

Compounds (I) of Examples 1-59.

[Compound I-11]

Compound (I) selected from

-   (6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 1);-   (6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 2);-   (3-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (compound of Example 3);-   (3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (compound of Example 4);-   (6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 5);-   (6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 6);-   (6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 7);-   (6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 8);-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 9);-   (3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (Optical Isomer) (compound of Example 10);-   (6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (optical isomer) (compound of Example 11);-   (6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (optical isomer) (compound of Example 17);-   (6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 18);-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 28);-   (3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetic    acid (Optical Isomer) (compound of Example 29);-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (compound of Example 36);-   (6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 49);-   (6-((1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 50); and-   (6-((1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic    acid (Optical Isomer) (compound of Example 52).

Examples of salts of compounds represented by the formula (I) includemetal salt, ammonium salt, salt with organic base, salt with inorganicacid, salt with organic acid, salt with basic or acidic amino acid andthe like.

Preferable examples of the metal salt include alkali metal salts such assodium salt, potassium salt and the like; alkaline earth metal saltssuch as calcium salt, magnesium salt, barium salt and the like; aluminumsalt and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like, and preferable examples of thesalt with acidic amino acid include salts with aspartic acid, glutamicacid and the like.

Among the above-mentioned salts, a pharmaceutically acceptable salt ispreferable.

Compound (I) may be a prodrug.

A prodrug of compound (I) means a compound which is converted tocompound (I) with a reaction due to an enzyme, an gastric acid, etc.under the physiological condition in the living body, that is, acompound which is converted to compound (I) by oxidation, reduction,hydrolysis, etc. due to an enzyme; a compound which is converted tocompound (I) by hydrolysis etc. due to gastric acid, etc.

Examples of the prodrug of compound (I) include a compound obtained bysubjecting amino in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting amino incompound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation); a compound obtained by subjecting hydroxy in compound(I) to an acylation, alkylation, phosphorylation or boration (e.g., acompound obtained by subjecting hydroxy in compound (I) to anacetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation ordimethylaminomethylcarbonylation); a compound obtained by subjectingcarboxy in compound (I) to an esterification or amidation (e.g., acompound obtained by subjecting carboxy in compound (I) to a C₆ alkylesterification, phenyl esterification, carboxymethyl esterification,dimethylaminomethyl esterification, pivaloyloxymethyl esterification,ethoxycarbonyloxyethyl esterification, phthalidyl esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification or methyl amidation etc.) andthe like. Among these, compound (I) wherein carboxy is esterified byC₁₋₆ alkyl such as methyl, ethyl, tert-butyl and the like is preferablyused. These compounds can be produced from compound (I) according to amethod known per se.

A prodrug for compound (I) may also be one which is converted tocompound (I) under a physiological condition, such as those described inIYAKUHIN no KAIHATSU, Development of Pharmaceuticals, Vol. 7, Design ofMolecules, p. 163-198, Published by HIROKAWA SHOTEN, 1990.

In the present specification, a prodrug may be in the form of a salt.Examples of the salt include those exemplified as the salt of thecompound represented by the aforementioned formula (I).

The production method of compound (I) is explained below.

The starting materials and reagents used and the compounds obtained ineach step of the following production methods may form each salt.Examples of such salt include those similar to the salts of theaforementioned compound (I) and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or other desired kind of salt by a method known per se.

The compound obtained in each step can also be used for the nextreaction in the form of the reaction mixture or after obtaining as acrude product. Alternatively, the compound obtained in each step can beisolated and/or purified from the reaction mixture by a separation meanssuch as concentration, crystallization, recrystallization, distillation,solvent extraction, fractionation, chromatography and the like accordingto conventional methods.

When the starting materials and reagent compounds in each step arecommercially available, such commercially available products can bedirectly used.

In the reaction of each step, the reaction time may vary depending onthe reagent and the solvent to be used. Unless particularly described,it is generally 1 min-48 hr, preferably 10 min-8 hr.

In the reaction of each step, the reaction temperature may varydepending on the reagent and solvent to be used. Unless particularlydescribed, it is generally −78° C. to 300° C., preferably −78° C. to150° C.

In the reaction of each step, the pressure may vary depending on thereagent and solvent to be used. Unless particularly described, it isgenerally 1 atm-20 atm, preferably 1 atm-3 atm.

In the reaction of each step, for example, Microwave synthesis apparatussuch as Initiator manufactured by Biotage and the like may be used. Thereaction temperature may vary depending on the reagent and solvent to beused. Unless particularly described, it is generally room temperature to300° C., preferably 50° C. to 250° C. While the reaction time variesdepending on the reagent and solvent to be used, unless particularlydescribed, it is generally 1 min-48 hr, preferably 1 min-8 hr.

In the reaction of each step, unless particularly described, a reagentis used in 0.5 equivalents-20 equivalents, preferably 0.8 equivalents-5equivalents, relative to the substrate. When a reagent is used as acatalyst, the reagent is used in 0.001 equivalent-1 equivalent,preferably 0.01 equivalent-0.2 equivalent, relative to the substrate.When a reagent also acts as a reaction solvent, the reagent is used in asolvent amount.

In the reaction of each step, unless particularly described, thereaction is performed without solvent, or by dissolving or suspending ina suitable solvent. Specific examples of the solvent include thesolvents described in the Examples and the following.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;

aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

saturated hydrocarbons: cyclohexane, hexane and the like;

amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

acid anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;

inorganic acids: hydrochloric acid, sulfuric acid and the like;

esters: ethyl acetate and the like;

ketones: acetone, methyl ethyl ketone and the like;

water.

Two or more kinds of the above-mentioned solvents may be mixed at anappropriate ratio and used.

When a base is used in the reaction of each step, for example, the basesshown below or the bases described in the Examples are used.

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;

basic salts: sodium carbonate, calcium carbonate, sodium hydrogencarbonate and the like;

organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;

metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like;

organic lithiums: n-butyllithium and the like.

When an acid or an acidic catalyst is used in the reaction of each step,for example, the acids and acidic catalysts shown below or the acids andacidic catalysts described in the Examples are used.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;

organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like;

Lewis acid: boron trifluoride diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

The reaction of each step is, unless otherwise specified, performed by amethod known per se, for example, the methods described in the FifthSeries of Experimental Chemistry, vol. 13-vol. 19 (The Chemical Societyof Japan ed.); Experimental Chemistry, vol. 14-vol. 15 (The ChemicalSociety of Japan ed.); Fine Organic Chemistry, rev. 2nd edition (L. F.Tietze, Th. Eicher, NANKODO); rev. Organic Name Reaction (Hideo Togo,Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & SonsInc); Modern Organic Synthesis in the Laboratory A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (ElsevierJapan); Strategic Applications of Named Reactions in Organic Synthesis(Kiyoshi Tomioka, supervisor of translation, KAGAKUDOJIN); ComprehensiveOrganic Transformations (VCH Publishers Inc.) 1989 and the like, or themethods described in the Examples.

When reduction reaction is performed in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney-nickel; Raney cobalt;hydrogen; formic acid and the like. When carbon-carbon double bond ortriple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like is available.

When oxidation reaction is performed in each step, examples of theoxidant to be used include peracids such as m-chloroperbenzoic acid(MCPBA), hydrogen peroxide, t-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; high valent iodine reagents such as iodosylbenzene and the like;reagents having manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents having chrome such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide-pyridine complex; osmium tetraoxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When radical cyclization reaction is performed in each step, examples ofthe radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. Examples of the radical reagent to be used includetributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane,diphenylsilane, samarium iodide and the like.

When Wittig reaction is performed in each step, examples of the Wittigreagent to be used include alkylidenephosphoranes and the like.Alkylidenephosphoranes can be prepared by a method known per se, forexample, by reacting a phosphonium salt and a strong base.

When Horner-Emmons reaction is performed in each step, examples of thereagent to be used include phosphonoacetic acid esters such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like;bases such as alkali metal hydrides, organic lithiums and the like.

When Friedel-Crafts reaction is performed in each step, examples of thereagent to be used include Lewis acid, acid chloride or alkylating agent(e.g., alkyl halides, alcohol, olefins and the like). Alternatively,organic acid or inorganic acid can also be used instead of the Lewisacid, and acid anhydrides such as acetic anhydride and the like can alsobe used instead of acid chloride.

When aromatic nucleophilic substitution reaction is performed in eachstep, the reagent includes nucleophilic agent (e.g., amines, imidazoleand the like) and base (e.g., basic salts, organic bases and the like).

When nucleophilic addition reaction by carbanion, nucleophilic1,4-addition reaction by carbanion (Michael addition reaction), ornucleophilic substitution reaction by carbanion is performed in eachstep, examples of the base to be used for developing carbanion includeorganic lithium, metal alkoxide, inorganic base, organic base and thelike.

When Grignard reaction is performed in each step, examples of theGrignard reagent include arylmagnesium halides such as phenylmagnesiumbromide and the like; and alkylmagnesium halides such as methylmagnesiumbromide and the like. The Grignard reagent can be prepared by a methodknown per se, for example, by reacting alkyl halide or aryl halide withmetal magnesium using ether or tetrahydrofuran as a solvent.

When Knoevenagel condensation reaction is performed in each step, thereagent includes an active methylene compound (e.g., malonic acid,diethyl malonate, malononitrile and the like) located between twoelectron-withdrawing groups and a base (e.g., organic bases, metalalkoxides, inorganic bases).

When Vilsmeier-Haack reaction is performed in each step, the reagentincludes phosphoryl chloride and amide derivative (e.g.,N,N-dimethylformamide and the like).

When azidation reaction of alcohol, alkyl halide, sulfonic acid ester isperformed in each step, examples of the azidation agent to be usedinclude diphenylphosphoryl azide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, when alcohols is azidated, a methodusing diphenylphosphoryl azide and 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU), a method using trimethylsilylazide and Lewis acid and the likeare used.

When reductive amination reaction is performed in each step, examples ofthe reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, the carbonyl compound to be used ispara-formaldehyde, aldehydes such as acetaldehyde and the like, orketones such as cyclohexanone and the like. When the substrate is acarbonyl compound, the amine to be used is ammonia, primary amine suchas methylamine and the like; secondary amine such as dimethylamine andthe like, or the like.

When Mitsunobu reaction is performed in each step, examples of thereagent include azodicarboxylates (e.g., diethyl azodicarboxylate(DEAD), diisopropyl azodicarboxylate (DIAD) and the like) andtriphenylphosphine.

When esterification reaction, amidation reaction, or ureation reactionis performed in each step, examples of the reagent to be used includehalogenated acyl forms such as acid chloride, acid bromide and the like;activated carboxylic acids such as acid anhydride, active ester form,sulfuric acid ester form and the like. As an activator of carboxylicacid, carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate condensing agentssuch as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphorylazide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt(BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);thionyl chloride; lower alkyl haloformates such as ethyl chloroformateand the like; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; or combination thereof andthe like can be mentioned. When a carbodiimide condensing agent is used,additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide(HOSu), dimethylaminopyridine (DMAP) and the like may be further addedto the reaction.

When coupling reaction is performed in each step, examples of the metalcatalyst to be used include palladium compounds such as palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; nickel compounds such astetrakis(triphenylphosphine)nickel (0) and the like; rhodium compoundssuch as tris(triphenylphosphine)rhodium(III) chloride and the like;cobalt compound; copper compounds such as copper oxide, copper(I) iodideand the like; platinum compound and the like. A base may be furtheradded to the reaction, and examples of such base include inorganicbases, basic salts and the like.

When thiocarbonylation reaction is performed in each step,representative example of the thiocarbonylating agent is diphosphoruspentasulfide. Besides diphosphorus pentasulfide, a reagent having a1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lowesson's reagent) and the like may also be used.

When Wohl-Ziegler reaction is performed in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. The reaction can be accelerated by adding heat,light, a radical initiator such as benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When halogenation reaction of the hydroxy group is performed in eachstep, examples of the halogenating agent to be used include acid halideof hydrohalic acid and inorganic acid, specifically, hydrochloric acid,thionyl chloride, phosphorus oxychloride and the like for chlorination,and 48% hydrobromic acid and the like for bromination. In addition, amethod of obtaining an alkyl halide form from alcohol by reactingtriphenylphosphine with carbon tetrachloride or carbon tetrabromide andthe like may also be used. Alternatively, a method of synthesizing analkyl halide form by two-step reactions including converting alcohol tosulfonic acid ester and reacting same with lithium bromide, lithiumchloride or sodium iodide may also be used.

When Arbuzov reaction is performed in each step, examples of the reagentto be used include alkyl halides such as ethyl bromoacetate and thelike; phosphites such as triethylphosphite, tri(isopropyl)phosphite andthe like.

When sulfonation reaction is performed in each step, examples of thesulfonating agent to be used include methanesulfonyl chloride,p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonicanhydride and the like.

When hydrolysis reaction is performed in each step, examples of thereagent include acid or base. When acid hydrolysis of t-butyl ester isperformed, formic acid, triethylsilane and the like may be added toreductively trap by-produced t-butyl cation.

When dehydration reaction is performed in each step, examples of thedehydrating agent to be used include sulfuric acid, phosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

In the present specification, the protecting group includes protectinggroup of hydroxyl group of alcohol and the like and phenolic hydroxylgroup, protecting group of carbonyl group of aldehyde, protecting groupof carbonyl group of ketone, protecting group of carboxyl group,thiol-protecting group, protecting group of amino group, protectinggroup of aromatic heterocycle such as imidazole, pyrrole, indole and thelike, and the like.

Here, X, Y¹, Y², Z, W, L, R¹, R² and R³ in the formulas in the followingreaction schemes are as defined above.

In any step of the production methods shown below, substituent on ring Acan be converted to a desired functional group by combining chemicalreactions known per se in each production method. The substituent onring A is not limited as long as it does not influence the reaction.Examples of the chemical reaction include oxidation reaction, reductionreaction, alkylation reaction, acylation reaction, ureation reaction,hydrolysis reaction, amination reaction, esterification reaction,coupling reaction, condensation reaction, deprotection reaction and thelike. These reactions are performed according to a method known per se.Examples of such method include the methods described in ORGANICFUNCTIONAL GROUP PREPARATIONS, 2nd edition, Academic Press (AcademicPress Inc.), 1989, or Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd edition, Wiley-VCH, 1999 and thelike, and the like.

Compound (I) can be produced from compound (2) by the method shown inreaction scheme 1.

wherein R⁴ is an optionally substituted C₁₋₆ alkyl group or anoptionally substituted C₇₋₁₆ aralkyl group, and other symbols are asdefined above.

In the present specification, the “optionally substituted C₇₋₁₆ aralkylgroup” is an “optionally substituted hydrocarbon group” wherein thehydrocarbon group is a “C₇₋₁₆ aralkyl group”.

Compound (2) can be produced from compound (10) by the method shown inreaction scheme 2.

wherein Y³, Y⁴, Y⁵ and Y⁶ are each an optionally protected hydroxylgroup or a leaving group (e.g., a halogen atom or —OSO₂Me,—OSO₂(4-tolyl), —OSO₂CF₃ and the like), Y⁷ is a hydroxyl group or ahalogen atom, and other symbols are as defined above. In the presentspecification, the optionally protected hydroxyl group is, for example,a hydroxyl group optionally protected by a hydroxy-protecting groupmentioned below.

Compound (2) wherein Y⁴ or Y⁶ is a leaving group can be produced by, forexample, an alkylation reaction of compound (5) with compound (3). Thisreaction is performed in the presence of a base in an inert solvent.Examples of the base include alkali metal hydride, inorganic base, basicsalt, alkali metal alkoxide, organic base, organic lithium, metal amideand the like.

Compound (2-1) can be produced from compound (11-1) by the method shownin reaction scheme 3.

wherein Y⁸ is a leaving group (e.g., a halogen atom or —OSO₂Me, —OSO₂(4-tolyl), —OSO₂CF₃ and the like), R⁵ is an optionally substitutedhydrocarbon group, P¹ is a protecting group, and other symbols are asdefined above.

Compound (2-1) can be produced by an alkylation reaction of compound(11-5). Alkylation reaction can be performed according to the methodshown in reaction scheme 2, or according thereto.

Compound (11-4-1) can be produced from compound (11-1) by the methodshown in reaction scheme 4.

wherein the symbols are as defined above.

Compound (3-1), compound (6) and compound (7) can be produced fromcompound (12-1) by the method shown in reaction scheme 5 or a methodanalogous thereto or the method exemplified in WO 2010/045258 or amethod analogous thereto. Compound (3-1) is compound (3) wherein Y⁷ is ahydroxyl group.

wherein Y⁹ is a halogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₁₋₆ alkoxy group or an optionallyprotected hydroxyl group, and other symbols are as defined above.

Compound (12) can be produced by converting the Meldrum's acid moiety ofcompound (12-5) to an ester. This reaction can be performed by reactingmethanol or ethanol in an inert solvent such as DMF and the like.

Compound (12) can be produced by an alkylation reaction of compound(12-6). Alkylation reaction can be performed according to the methodshown in reaction scheme 2, or according thereto.

Compound (12) can be produced by a cyclopropanation reaction of theolefin moiety of compound (12-3). This reaction can be performedaccording to a method including reacting compound (12-3) and adiazoacetic acid ester in the presence of a catalyst (e.g., rhodiumcatalyst, ruthenium catalyst, copper catalyst etc.).

Compound (12-1-1) can be produced from compound (13-1) by the methodshown in reaction scheme 6. Compound (12-1-1) is compound (12-1) whereinY² is a nitrogen atom and X is an oxygen atom.

wherein Y¹⁰ is an optionally protected hydroxyl group, and other symbolsare as defined above.

Compound (13-3) can be produced by a homologation reaction of compound(13-2) with N,N-dimethylformamide dimethyl acetal and the like.

Compound (13-4) can be produced by an intramolecular cyclizationreaction of compound (13-3) using an acid. As the acid to be used,hydrochloric acid and the like can be mentioned.

Compound (12-1-2) can be produced from compound (13-6) by the methodshown in reaction scheme 7 or a method analogous thereto or the methodexemplified in WO 2010/045258 or a method analogous thereto. Compound(12-1-2) is compound (12-1) wherein Y² is a nitrogen atom and X is abond.

wherein R⁶, R⁷ are each an optionally substituted C₁₋₆ alkyl group or anoptionally substituted C₇₋₁₆ aralkyl group, Y¹¹ is a leaving group, andother symbols are as defined above.

Compound (13-9) can be produced by an intramolecular cyclizationreaction of compound (13-8) using a base. The base to be used includessodium hydride and the like.

Compound (12-1-2) can be produced by a decarboxylation reaction ofcompound (13-9) by heating in DMSO/water solvent.

Compound (4-1) can be produced from compound (10) by the method shown inreaction scheme 8. Compound (4-1) is compound (4) wherein Y⁴ is ahydroxyl group.

wherein R⁸ is an optionally substituted C₁₋₆ alkyl group or anoptionally substituted C₇₋₁₆ aralkyl group, and other symbols are asdefined above.

Compound (15-1) and compound (4-1-1) can be produced from compound(11-1) by the method shown in reaction scheme 9.

wherein the symbols are as defined above.

Compound (15-1) and compound (17-5) can be produced by an alkylationreaction of compound (16-4) and compound (17-4). Alkylation reaction canbe performed according to the method shown in reaction scheme 2, oraccording thereto.

Compound (4-1-2) can be produced from compound (18-1) by the methodshown in reaction scheme 10.

wherein the symbols are as defined above.

Compound (18-4) can be produced from compound (18-3) by, for example,the method described in Tetrahedron Letters, 2012, 53, pages 5503-5506or according thereto. As the trifluoromethylating agent to be used,1-trifluoromethyl-1,2-benzoiodoxol-3(1H)-one and the like can bementioned. As the catalyst, copper(I) iodide,tetrakis(acetonitrile)copper(I) hexafluorophosphate and the like can bementioned. Furthermore, an acid may be added to the reaction and, assuch acid, p-toluenesulfonic acid and the like can be mentioned.

Compound (5-1) and compound (4-1-3) can be produced from compound (11-6)and compound (17-1) by the method shown in reaction scheme 11. Compound(5-1) and compound (4-1-3) are compound (5) and compound (4-1) wherein Wis Ar. Here, Ar is an optionally substituted heterocyclic group or anoptionally substituted C₆₋₁₄ aryl group.

wherein the symbols are as defined above.

Compound (19-1) and compound (20-1) can be produced by a borationreaction of compound (11-6) and compound (17-1). As the base to be used,organic lithiums and the like can be mentioned. As the borating agent tobe used, trimethyl borate, triisopropyl borate and the like can bementioned.

Compound (4-1-4) can be produced from compound (18-2) by the methodshown in reaction scheme 12.

wherein R⁹ is an optionally substituted hydrocarbon group, and othersymbols are as defined above.

Compound (21-1) can be produced by a dehydration reaction of compound(21-2). As the dehydrating agent to be used, methylN-(triethylammoniumsulfonyl)carbamate and the like can be mentioned.

Compound (4-1-5) can be produced from compound (22-1) by the methodshown in reaction scheme 13.

wherein R¹⁰ is a hydrogen atom or an optionally substituted hydrocarbongroup, and other symbols are as defined above.

Compound (22-3) can be produced by an addition reaction of atrifluoromethyl group by compound (22-2) andtrimethyl(trifluoromethyl)silane and tetrabutylammonium fluoride.

Compound (22-4) can be produced by a dehydration reaction of compound(22-3). Dehydration reaction can be performed by the method shown inreaction scheme 12, or according thereto.

Compound (4-1-6) can be produced from compound (23-1) by the methodshown in reaction scheme 14.

wherein R¹¹ is an optionally substituted C₁₋₆ alkyl group or anoptionally substituted C₇₋₁₆ aralkyl group, R¹² and R¹³ are each anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₇₋₁₆aralkyl group or an optionally substituted C₆₋₁₄ aryl group, and othersymbols are as defined above.

Compound (24), compound (24-1) and compound (24-2) can be produced fromcompound (25-1) by the method shown in reaction scheme 15.

wherein P² is a protecting group, R¹⁴, R¹⁵ and R¹⁶ are each a hydrogenatom, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₇₋₁₆ aralkyl group or an optionally substituted C₆₋₁₄ arylgroup, and other symbols are as defined above.

Compound (25-3) and compound (24) can be produced by an alkylationreaction of compound (25-2) and compound (25-1). Alkylation reaction canbe performed according to the method shown in reaction scheme 2, oraccording thereto.

Compound (24-3) can be produced from compound (25-5) by the method shownin reaction scheme 16.

wherein R¹⁷ is a substituent, and other symbols are as defined above.

Compound (24-3) can be produced by the reaction of compound (25-6) withcompound (25-1). The reaction is performed in the presence of phosphaterepresented by bromotris(pyrrolidino)phosphonium hexafluorophosphate(PyBrop) and a base. Examples of the base include alkali metal hydride,inorganic base, basic salt, alkali metal alkoxide, organic base, organiclithium, metal amide and the like.

Compound (10-1) can be produced from compound (26-1) by the method shownin reaction scheme 17.

wherein P³ and P⁴ are protecting groups, R¹⁸ and R¹⁹ are each anoptionally substituted hydrocarbon group, and other symbols are asdefined above.

Compound (26-2) can be produced by halogenation reaction of compound(26-1). As the base to be used, organic lithiums and the like can bementioned; and as the halogenating agent, iodine, bromine,N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS),1,2-dibromo-1,1,2,2-tetrafluoroethane and the like can be mentioned.

Compound (10-1) can be produced by alkylation of the hydroxyl group ofcompound (26-5). In this reaction, alkyl halide and the like are reactedin the presence of silver oxide and the like in an inert solvent such astoluene and the like.

Compound (10-2) can be produced from compound (27) by the method shownin reaction scheme 18.

wherein the symbols are as defined above.

In each of the aforementioned reactions, when the starting compound hasan amino group, a carboxy group, a hydroxy group, a carbonyl group or amercapto group as a substituent, a protecting group generally used inthe peptide chemistry and the like may be introduced into these groups,and the object compound can be obtained by eliminating the protectinggroup as necessary after the reaction.

Examples of the amino-protecting group include a formyl group; a C₁₋₆alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group, a benzoyl group, aC₇₋₁₀ aralkyl-carbonyl group (e.g., benzylcarbonyl), a C₇₋₁₄aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,9-fluorenylmethoxycarbonyl), a trityl group, a phthaloyl group, anN,N-dimethylaminomethylene group, a substituted silyl group (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), a C₂₋₆ alkenyl group(e.g., 1-allyl) and the like. These groups are optionally substituted by1 to 3 substituents selected from a halogen atom, a C₁₋₆ alkoxy groupand a nitro group.

Examples of the carboxyl-protecting group include a C₁₋₆ alkyl group, aC₇₋₁₁ aralkyl group (e.g., benzyl), a phenyl group, a trityl, asubstituted silyl group (e.g., trimethylsilyl, triethylsilyl,dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), aC₂₋₆ alkenyl group (e.g., 1-allyl) and the like. These groups areoptionally substituted by 1 to 3 substituents selected from a halogenatom, a C₁₋₆ alkoxy group and a nitro group.

Examples of the hydroxy-protecting group include a C₁₋₆ alkyl group, aphenyl group, a trityl group, a C₇₋₁₀ aralkyl group (e.g., benzyl), aformyl group, a C₁₋₆ alkyl-carbonyl group, a benzoyl group, a C₇-10aralkyl-carbonyl group (e.g., benzylcarbonyl), a 2-tetrahydropyranylgroup, a 2-tetrahydrofuranyl group, a substituted silyl group (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), a C₂₋₆ alkenyl group(e.g., 1-allyl), and the like. These groups are optionally substitutedby 1 to 3 substituents selected from a halogen atom, a C₁₋₆ alkyl group,a C₁₋₆ alkoxy group and a nitro group.

Examples of the carbonyl-protecting group include a cyclic acetal (e.g.,1,3-dioxane), a non-cyclic acetal (e.g., a di-C₁₋₆ alkylacetal) and thelike.

Examples of the mercapto-protecting group include a C₁₋₆ alkyl group, aphenyl group, a trityl group, a C₇₋₁₀ aralkyl group (e.g., benzyl), aC₁₋₆ alkyl-carbonyl group, a benzoyl group, a C₇₋₁₀ aralkyl-carbonylgroup (e.g., benzylcarbonyl), a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl), a C₇₋₁₄aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,9-fluorenylmethoxycarbonyl), a 2-tetrahydropyranyl group, a C₁₋₆alkylamino-carbonyl group (e.g., methylaminocarbonyl,ethylaminocarbonyl) and the like. These groups are optionallysubstituted by 1 to 3 substituents selected from a halogen atom, a C₁₋₆alkyl group, a C₁₋₆ alkoxy group and a nitro group.

The above-mentioned protecting groups can be removed by a method knownper se, for example, the method described in Protective Groups inOrganic Synthesis, John Wiley and Sons (1980) and the like.Specifically, a method using acid, base, ultraviolet rays, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyliodide, trimethylsilyl bromide) and the like, a reduction method and thelike can be mentioned.

In compound (I) obtained by each of the above-mentioned productionmethods, a functional group in a molecule can also be converted to adesired functional group by a combination of chemical reactions knownper se. Examples of the chemical reaction include oxidation reaction,reduction reaction, alkylation reaction, acylation reaction, ureationreaction, hydrolysis reaction, amination reaction, esterificationreaction, aryl coupling reaction, deprotection reaction and the like.

Compound (I) obtained by each of the above-mentioned production methodscan be isolated and purified by a known means such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like. In addition, the starting compounds used for each of theabove-mentioned production methods can be isolated and purified by aknown means similar to the aforementioned methods. These startingcompounds may be used in the form of a reaction mixture withoutisolation, as a starting material for the next step.

When compound (I) contains an isomer such as an optical isomer, astereoisomer, a regioisomer or a rotamer, any one of them and a mixturethereof are also encompassed in compound (I) For example, when compound(I) contains an optical isomer, an optical isomer resolved from racemateis also encompassed in compound (I). Each of these isomers can beobtained as a single product by a synthesis means, separation means(e.g., concentration, solvent extraction, column chromatography,recrystallization etc.), optical resolution means (e.g., fractionalrecrystallization method, chiral column method, diastereomer methodetc.) and the like, which are known per se.

Compound (I) may be a crystal, and the crystal form may be single or amixture of crystal forms, both of which are encompassed in compound (I).The crystal can be produced by a crystallization method known per se.

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

In the present specification, the melting point means that measuredusing, for example, a micromelting point apparatus (Yanako, MP-500D orBuchi, B-545), a DSC (differential scanning calorimetry) device (SEIKO,EXSTAR6000) or the like.

In general, the melting points vary depending on the measurementapparatuses, the measurement conditions and the like. The crystal in thepresent specification may show different values from the melting pointdescribed in the present specification, as long as they are within eachof a general error range.

The crystal of the present invention is superior in physicochemicalproperties (e.g., melting point, solubility, stability) and biologicalproperties (e.g., pharmacokinetics (absorption, distribution,metabolism, excretion), efficacy expression), and thus it is extremelyuseful as a medicament.

Compound (I) may be a solvate (e.g., hydrate etc.), or a non-solvate(e.g., non-hydrate etc.), and both are encompassed in compound (I).

A compound labeled with an isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸F, ³⁵S, ¹²⁵Ietc.) and the like is also encompassed in compound (I).

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Compound (I) labeled or substituted with an isotope can be used as, forexample, a tracer (PET tracer) used for Positron Emission Tomography(PET), and may be useful in the fields of medical diagnosis and thelike.

Compound (I) and a prodrug thereof (hereinafter, these are collectivelyabbreviated as the compound of the present invention) may have a GPR40receptor function modulating action, particularly, a GPR40 agonistactivity. GPR40 agonist activates GPR40 expressed in pancreatic β cellsto promote insulin secretion, and may activate GPR40 expressed in theintestine to promote glucagon-like peptide-1 (glucagon-like peptide-1;GLP-1) secretion. That is, the compound of the present invention mayhave a hypoglycemic action, an insulin secretagogue action, a GLP-1secretagogue action and a pancreatic β cell protecting action. The GLP-1secretagogue action of the compound of the present invention can bemeasured using, for example, an ELISA kit containing a GLP-1 antibody.Moreover, the compound of the present invention may have aglucose-dependent insulinotropic polypeptide (GIP) secretagogue action,a food ingestion suppressive action and a glucagon secretion suppressiveaction.

The compound of the present invention may be expected to show lowtoxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity,reproductive toxicity, cardiotoxicity, carcinogenicity, cytotoxicity)and can be safely administered a mammal (e.g., mouse, rat, hamster,rabbit, cat, dog, bovine, sheep, monkey, human) directly or as apharmaceutical composition by mixing same with a pharmacologicallyacceptable carrier and the like.

The compound of the present invention may be useful as modulators ofphysiological function in which GPR40 receptor is involved or as agentsfor the prophylaxis or treatment of pathology or disease in which GPR40receptor is involved.

To be specific, the compound of the present invention may be useful asan agent for the prophylaxis or treatment of diabetes (e.g., type 1diabetes, type 2 diabetes, gestational diabetes, obese diabetes), aninsulin secretagogue, a pancreatic β cell protector, a GLP-1 secretionpromoter, a GIP secretion promoter, an agent for the prophylaxis ortreatment of impaired glucose tolerance (IGT) and an agent forpreventing progression of impaired glucose tolerance to diabetes.

Particularly, the compound of the present invention may be useful asblood glucose level-dependent insulin secretagogues based on the GPR40agonist activity thereof. That is different from sulfonylureas, thecompound of the present invention may be useful as insulin secretagoguesthat do not cause hypoglycemia.

Furthermore, the compound of the present invention may be used as anagent for the prophylaxis or treatment of obesity, hyperlipidemia (e.g.,hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia,hypo HDL-cholesterolemia, postprandial hyperlipidemia), hypertension,cardiac failure, diabetic complications [e.g., neuropathy, nephropathy,diabetic retinopathy, diabetic cardiomyopathy, cataract,macroangiopathy, osteopenia, hyperosmolar diabetic coma, infections(e.g., respiratory infection, urinary tract infection, gastrointestinalinfection, dermal soft tissue infections, inferior limb infection),diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder,peripheral blood circulation disorder], metabolic syndrome (according tothe diagnostic criteria for Japanese people as reported in 2005 by theJapan Society for the Study of Obesity and the like, the metabolicsyndrome refers to males having an abdominal circumference of 85 cm orabove and females having an abdominal circumference of 90 cm or aboveand satisfying two items out of three items of: systolic blood pressureof not less than 130 or diastolic blood pressure of not less than 85mmHg, neutral triglyceride not less than 150 mg/dl or HDLc less than 40mg/dl, and fasting blood sugar level (venous plasma glucoseconcentration) not less than 110 mg/dl) and the like.

For diagnostic criteria of diabetes, Japan Diabetes Society reporteddiagnostic criteria in 1999.

According to this report, diabetes is a condition showing any of afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test(75 g OGTT) 2 h level (glucose concentration of intravenous plasma) ofnot less than 200 mg/dl, and a non-fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 200 mg/dl. Acondition not falling under the above-mentioned diabetes and differentfrom “a condition showing a fasting blood glucose level (glucoseconcentration of intravenous plasma) of less than 110 mg/dl or a 75 goral glucose tolerance test (75 g OGTT) 2 h level (glucose concentrationof intravenous plasma) of less than 140 mg/dl” (normal type) is called a“borderline type”.

In addition, ADA (American Diabetes Association) and WHO reporteddiagnostic criteria of diabetes.

According to these reports, diabetes is a condition showing a fastingblood glucose level (glucose concentration of intravenous plasma) of notless than 126 mg/dl, or a 75 g oral glucose tolerance test 2 h level(glucose concentration of intravenous plasma) of not less than 200mg/dl.

According to the above-mentioned reports by ADA and WHO, impairedglucose tolerance is a condition showing a 75 g oral glucose tolerancetest 2 h level (glucose concentration of intravenous plasma) of not lessthan 140 mg/dl and less than 200 mg/dl. According to the report of ADA,a condition showing a fasting blood glucose level (glucose concentrationof intravenous plasma) of not less than 110 mg/dl and less than 126mg/dl is called IFG (Impaired Fasting Glucose). According to the reportof WHO, among the IFG (Impaired Fasting Glucose), a condition showing afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 110 mg/dl and less than 126 mg/dl is called IFG(Impaired Fasting Glycemia).

The compound of the present invention may also be useful as an agent forthe prophylaxis or treatment of diabetes, borderline type, impairedglucose tolerance, IFG (Impaired Fasting Glucose) and IFG (ImpairedFasting Glycemia), as determined according to the above-mentioneddiagnostic criteria. Moreover, the compound of the present invention canprevent progress of borderline type, impaired glucose tolerance, IFG(Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) intodiabetes.

The compound of the present invention may also be useful as atherapeutic agent for diabetes with sulfonylurea secondary failure andmay afford a superior insulin secretion effect and a hypoglycemic effectfor diabetic patients for whom sulfonylurea compounds and fast-actinginsulin secretagogues fail to provide an insulin secretion effect, andtherefore, fail to provide a sufficient hypoglycemic effect.

As the sulfonylurea compound here, a compound having a sulfonylureaskeleton or a derivative thereof (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, glipizide, glybuzole and the like) can be mentioned.

As the fast-acting insulin secretagogue, a compound that promotesinsulin secretion from pancreatic B cell in the same manner as asulfonylurea compound, though it does not have a sulfonylurea skeleton,such as glinide compounds (e.g., repaglinide, senaglinide, nateglinide,mitiglinide or a calcium salt hydrate thereof etc.), and the like, canbe mentioned.

The compound of the present invention may also be useful as an agent forthe prophylaxis or treatment of, for example, cognitive impairment,osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia,diabetic cachexia, hemopathic cachexia, endocrinopathic cachexia,infectious cachexia or cachexia induced by acquired immunodeficiencysyndrome), fatty liver, polycystic ovary syndrome, renal disease (e.g.,diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephroticsyndrome, hypertensive nephrosclerosis, end-stage renal disorder),muscular dystrophy, myocardial infarction, angina pectoris,cerebrovascular disorder (e.g., cerebral infarction, cerebral apoplexy),insulin resistance syndrome, syndrome X, hyperinsulinemia, perceptiondisorder in hyperinsulinemia, tumor (e.g., leukemia, breast cancer,prostate cancer, skin cancer), irritable bowel syndrome, acute orchronic diarrhea, inflammatory disease (e.g., arteriosclerosis (e.g.,atherosclerosis), rheumatoid arthritis, spondylitis deformans,osteoarthritis, lumbago, gout, postoperative or post-traumaticinflammation, swelling, neuralgia, pharyngolaryngitis, bladderinflammation, hepatitis (including nonalcoholic steatohepatitis),pneumonia, pancreatitis, inflammatory colitis, ulcerative colitis,chronic obstructive pulmonary diseases (COPD)), visceral fat syndrome,foot ulcer, sepsis, psoriasis and the like.

In addition, the compound of the present invention can also be used forthe improvement of the symptoms of abdominal pain, nausea, vomiting,uncomfortable feeling in the upper abdomen and the like, which areassociated with peptic ulcer, acute or chronic gastritis, biliarydyskinesia, cholecystitis and the like, and the like.

Based on a pancreatic β cell protection action of the compound of thepresent invention, it can be used for the prognosis improvement inpancreatic islet transplantation.

The compound of the present invention may also be useful for decreasingthe visceral fat, suppressing visceral fat accumulation, improving sugarmetabolism, improving lipid metabolism, insulin sensitizing, suppressingoxidized LDL production, improving lipoprotein metabolism, improvingcoronary metabolism, preventing or treating cardiovascular complication,preventing or treating heart failure complication, decreasing bloodremnant, preventing or treating anovulation, preventing or treatinghirsutism, preventing or treating hyperandrogenism and the like.

The compound of the present invention may also be used for the secondaryprevention and the suppression of progression of the above-mentionedvarious diseases (e.g., cardiovascular event such as myocardialinfarction and the like).

A medicament containing the compound of the present invention can besafely administered solely to a mammal or by mixing with apharmacologically acceptable carrier according to a method known per se(e.g., the method described in the Japanese Pharmacopoeia etc.) as theproduction method of a pharmaceutical preparation, and in the form of,for example, tablet (including sugar-coated tablet, film-coated tablet,sublingual tablet, orally disintegrating tablet, buccal tablet and thelike), pill, powder, granule, capsule (including soft capsule,microcapsule), troche, syrup, liquid, emulsion, suspension, releasecontrol preparation (e.g., immediate-release preparation,sustained-release preparation, sustained-release microcapsule), aerosol,film (e.g., orally disintegrating film, oral mucosa-adhesive film),injection (e.g., subcutaneous injection, intravenous injection,intramuscular injection, intraperitoneal injection), drip infusion,transdermal absorption type preparation, ointment, lotion, adhesivepreparation, suppository (e.g., rectal suppository, vaginalsuppository), pellet, nasal preparation, pulmonary preparation(inhalant), eye drop and the like, orally or parenterally (e.g.,intravenous, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intrarectal, intravaginal,intraperitoneal and intratumor administrations, administration to thevicinity of tumor, and direct administration to the lesion).

During production of an oral preparation, coating may be applied asnecessary for the purpose of masking of taste, enteric property ordurability.

Examples of the coating base to be used for coating include sugarcoating base, aqueous film coating base, enteric film coating base andsustained-release film coating base.

As the sugar coating base, sucrose is used. Moreover, one or more kindsselected from talc, precipitated calcium carbonate, gelatin, gum arabic,pullulan, carnauba wax and the like may be used in combination.

Examples of the aqueous film coating base include cellulose polymerssuch as hydroxypropyl cellulose, hydroxypropylmethyl cellulose,hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; syntheticpolymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidoneetc.; and polysaccharides such as pullulan etc.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, celluloseacetate phthalate etc.; acrylic polymers such as methacrylic acidcopolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD[Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [EudragitS (trade name)] etc.; and naturally occurring substances such as shellacetc.

Examples of the sustained-release film coating base include cellulosepolymers such as ethyl cellulose etc.; and acrylic polymers such asaminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethylacrylate-methyl methacrylate copolymer suspension [Eudragit NE (tradename)] etc.

The above-mentioned coating bases may be used after mixing with two ormore kinds thereof at appropriate ratios. For coating, for example, alight shielding agent such as titanium oxide, red ferric oxide and thelike can be used.

The content of the compound of the present invention in a pharmaceuticalpreparation is about 0.01 to about 100% by weight relative to the wholepreparation. While the dose of the compound of the present inventionvaries depending on the administration subject, administration route,diseases, condition and the like, for example, the compound of thepresent invention (as an active ingredient) can be orally administeredto a patient with diabetes (body weight about 60 kg) in about 0.01 toabout 30 mg/kg body weight per day, preferably about 0.1 to about 20mg/kg body weight per day, more preferably about 1 to about 20 mg/kgbody weight per day, which may be given at once or in several portions(e.g., 1-3 portions) a day.

As the above-mentioned pharmacologically acceptable carrier, variousorganic or inorganic carrier substances conventionally used as apreparation material can be mentioned. For example, excipient,lubricant, binder and disintegrant for solid preparations; solvent,solubilizing agents, suspending agent, isotonic agent, buffer andsoothing agent for liquid preparations and the like can be mentioned.Where necessary, conventional additives such as preservatives,antioxidants, colorants, sweetening agents, adsorbing agents, wettingagents and the like can be used.

As the excipient, for example, lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light anhydrous silicic acid and thelike can be mentioned.

As the lubricant, for example, magnesium stearate, calcium stearate,talc, colloidal silica and the like can be mentioned.

As the binder, for example, crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose,carboxymethylcellulose sodium and the like can be mentioned.

As the disintegrant, for example, starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose and the like can be mentioned.

As the solvent, for example, water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like can bementioned.

As the solubilizing agents, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate and thelike can be mentioned.

As the suspending agent, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like, and the like can be mentioned.

As the isotonic agent, for example, glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like can be mentioned.

As the buffer, for example, buffers such as phosphates, acetates,carbonates, citrates and the like, and the like can be mentioned.

As the soothing agent, for example, benzyl alcohol and the like can bementioned.

As the preservative, for example, p-hydroxybenzoates, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid andthe like can be mentioned.

As the antioxidant, for example, sulfites, ascorbic acid, α-tocopheroland the like can be mentioned.

As the colorant, for example, water-soluble edible tar pigments (e.g.,food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos.4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insolublelake pigments (e.g., aluminum salt of the aforementioned water-solubleedible tar pigment and the like), natural pigments (e.g., β-carotene,chlorophil, red iron oxide etc.) and the like can be mentioned.

As the sweetening agent, for example, saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia and the like can be mentioned.

Moreover, the compound of the present invention can be used incombination with drugs other than the compound of the present invention.

As the drugs that can be used in combination with the compound of thepresent invention (hereinafter sometimes to be abbreviated as aconcomitant drug), for example, therapeutic agents for diabetes,therapeutic agents for diabetic complications, therapeutic agents forhyperlipidemia, antihypertensive agents, antiobesity agents, diuretics,chemotherapeutic agents, immunotherapeutic agents, antiinflammatoryagents, antithrombotic agents, therapeutic agents for osteoporosis,vitamins, antidementia agents, erectile dysfunction improving drugs,therapeutic agents for pollakisuria or anischuria, therapeutic agentsfor dysuria and the like can be mentioned. Specifically, the followingagents can be mentioned.

Examples of therapeutic agents for diabetes include insulin preparations(e.g., animal insulin preparations extracted from pancreas of bovine orswine; human insulin preparations genetically synthesized usingEscherichia coli or yeast; zinc insulin; protamine zinc insulin;fragment or derivative of insulin (e.g., INS-1), oral insulinpreparation), insulin sensitizers (e.g., pioglitazone or a salt thereof(preferably hydrochloride), rosiglitazone or a salt thereof (preferablymaleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone,Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505,THR-0921, the compound described in WO 2007/013694, WO 2007/018314, WO2008/093639 and WO 2008/099794), α-glucosidase inhibitors (e.g.,voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., metformin,buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)),insulin secretagogues [sulfonylurea (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, glipizide, glybuzole), repaglinide, nateglinide,mitiglinide or calcium salt hydrate thereof], dipeptidyl-peptidase IVinhibitors (e.g., Alogliptin or a salt thereof (preferably benzoate),Vildagliptin, Sitagliptin, Saxagliptin, BI1356, GRC8200, MP-513,PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104,Trelagliptin or a salt thereof (preferably, succinate)), β3 agonist(e.g., N-5984), GPR40 agonist (e.g., Fasiglifam or a hydrate thereof(preferably, 0.5 hydrate), the compound described in WO 2004/041266, WO2004/106276, WO 2005/063729, WO 2005/063725, WO 2005/087710, WO2005/095338, WO 2007/013689 and WO 2008/001931), GLP-1 receptor agonists(e.g., GLP-1, GLP-1 MR agent, Liraglutide, Exenatide, AVE-0010,BIM-51077, Aib(8,35)hGLP-1(7,37)NH₂, CJC-1131, Albiglutide), amylinagonists (e.g., pramlintide), phosphotyrosine phosphatase inhibitors(e.g., sodium vanadate), gluconeogenesis inhibitors (e.g., glycogenphosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagonantagonists, FBPase inhibitors), SGLT2 (sodium-glucose cotransporter 2)inhibitors (e.g., Depagliflozin, Canagliflozin, Empagliflozin,Ipragliflozin, Tofogliflozin, PF-04971729, TS-071), SGLT1 inhibitor,11β-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498,INCB-13739), adiponectin or agonist thereof, IKK inhibitors (e.g.,AS-2868), leptin resistance improving drugs, somatostatin receptoragonists, glucokinase activators (e.g., Piragliatin, AZD1656, AZD6370,TTP-355, the compound described in WO 2006/112549, WO 2007/028135, WO2008/047821, WO 2008/050821, WO 2008/136428 and WO 2008/156757), GIP(Glucose-dependent insulinotropic peptide), GPR119 agonists (e.g.,PSN821, MBX-2982, APD597), FGF21, FGF analogue and the like.

Examples of the therapeutic agents for diabetic complications includealdose reductase inhibitors (e.g., Tolrestat, Epalrestat, Zopolrestat,Fidarestat, CT-112, ranirestat (AS-3201), Lidorestat), neurotrophicfactors and increasing drugs thereof (e.g., NGF, NT-3, BDNF,neurotrophin production-secretion promoters described in WO01/14372(e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole),compound described in WO 2004/039365), PKC inhibitors (e.g.,ruboxistaurin mesylate), AGE inhibitors (e.g., ALT-946,N-phenacylthiazolium bromide (ALT-766), EXO-226, Pyridorin,Pyridoxamine), GABA receptor agonists (e.g., gabapentin, Pregabalin),serotonin⋅noradrenaline reuptake inhibitors (e.g., duloxetine), sodiumchannel inhibitors (e.g., Lacosamide), active oxygen scavengers (e.g.,thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine),somatostatin receptor agonists (BIM23190), apoptosis signal regulatingkinase-1 (ASK-1) inhibitors and the like.

Examples of the therapeutic agent for hyperlipidemia include HMG-CoAreductase inhibitors (e.g., pravastatin, simvastatin, lovastatin,atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof(e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g.,compound described in WO97/10224, for example,N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-aceticacid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate), anion exchange resins (e.g., colestyramine), probucol,nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), ethylicosapentate, phytosterol (e.g., soysterol, gamma oryzanol), cholesterolabsorption inhibitors (e.g., Zetia), CETP inhibitors (e.g., dalcetrapib,anacetrapib), ω-3 fatty acid preparations (e.g., ω-3-acid ethyl esters90) and the like.

Examples of the antihypertensive agent include angiotensin convertingenzyme inhibitors (e.g., captopril, enalapril, delapril and the like),angiotensin II antagonists (e.g., candesartan cilexetil, candesartan,losartan, losartan potassium, eprosartan, valsartan, telmisartan,irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan,azilsartan medoxomil and the like), calcium antagonists (e.g.,manidipine, nifedipine, amlodipine, efonidipine, nicardipine,cilnidipine and the like), R blockers (e.g., metoprolol, atenolol,propranolol, carvedilol, pindolol and the like), clonidine and the like.

Examples of the antiobesity agent include monoamine uptake inhibitors(e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine),serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptorantagonists, histamine H3 receptor modulator, GABA modulator (e.g.,topiramate), neuropeptide Y antagonists (e.g., velneperit), cannabinoidreceptor antagonists (e.g., rimonabant, taranabant), ghrelinantagonists, ghrelin receptor antagonists, ghrelin acylation enzymeinhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexinreceptor antagonists, melanocortin 4 receptor agonists,11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017), pancreaticlipase inhibitors (e.g., orlistat, cetilistat), β agonists (e.g.,N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoAcarboxylase (ACC) inhibitors, stearoyl-CoA desaturated enzymeinhibitors, microsomal triglyceride transfer protein inhibitors (e.g.,R-256918), Na-glucose cotransporter inhibitors (e.g., JNJ-28431754,remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g.,GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (e.g.,sodium vanadate, Trodusquemin), GPR119 agonists (e.g., PSN821, MBX-2982,APD597), glucokinase activators (e.g., AZD-1656), leptin, leptinderivatives (e.g., metreleptin), CNTF (ciliary neurotrophic factor),BDNF (brain-derived neurotrophic factor), cholecystokinin agonists,glucagon-like peptide-1 (GLP-1) preparations (e.g., animal GLP-1preparations extracted from the pancreas of bovine or swine; human GLP-1preparations genetically synthesized using Escherichia coli or yeast;fragments or derivatives of GLP-1 (e.g., exenatide, liraglutide)),amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Yagonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339,TM-30335), oxyntomodulin preparations: FGF21 preparations (e.g., animalFGF21 preparations extracted from the pancreas of bovine or swine; humanFGF21 preparations genetically synthesized using Escherichia coli oryeast; fragments or derivatives of FGF21), anorexigenic agents (e.g.,P-57) and the like.

Examples of the diuretics include xanthine derivatives (e.g., sodiumsalicylate and theobromine, calcium salicylate and theobromine),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide,methyclothiazide), antialdosterone preparations (e.g., spironolactone,triamterene), carbonate dehydratase inhibitors (e.g., acetazolamide),chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside,indapamide), azosemide, isosorbide, etacrynic acid, piretanide,bumetanide, furosemide and the like.

Examples of the chemotherapeutic agents include alkylating agents (e.g.,cyclophosphamide, ifosfamide), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil), antitumor antibiotics (e.g., mitomycin,adriamycin), plant-derived antitumor drugs (e.g., vincristine,vindesine, Taxol), cisplatin, carboplatin, etoposide and the like. Ofthese, Furtulon or NeoFurtulon, which are 5-fluorouracil derivatives,and the like are preferable.

Examples of the immunotherapeutic agents include microorganism orbacterial components (e.g., muramyl dipeptide derivatives, Picibanil),polysaccharides having immunity potentiating activity (e.g., lentinan,schizophyllan, krestin), cytokines obtained by genetic engineeringtechniques (e.g., interferon, interleukin (IL)), colony stimulatingfactors (e.g., granulocyte colony stimulating factor, erythropoietin)and the like, with preference given to interleukins such as IL-1, IL-2,IL-12 and the like.

Examples of the antiinflammatory agents include non-steroidalantiinflammatory agents such as aspirin, acetaminophen, indomethacin andthe like.

Examples of the antithrombotic agents include heparin (e.g., heparinsodium, heparin calcium, enoxaparin sodium, dalteparin sodium),warfarins (e.g., warfarin potassium), anti-thrombin drugs (e.g.,argatroban, dabigatran)), FXa inhibitors (e.g., rivaroxaban, apixaban,edoxaban, YM150, the compound described in WO 02/06234, WO 2004/048363,WO 2005/030740, WO 2005/058823 and WO 2005/113504), thrombolytic agents(e.g., urokinase, tisokinase, alteplase, nateplase, monteplase,pamiteplase), platelet aggregation inhibitors (e.g., ticlopidinehydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol,ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) andthe like.

Examples of the therapeutic agents for osteoporosis includealfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol,ipriflavone, pamidronate disodium, alendronate sodium hydrate,incadronate disodium, risedronate disodium and the like.

Examples of the vitamins include vitamin B₁, vitamin B₁₂ and the like.

Examples of the antidementia drugs include tacrine, donepezil,rivastigmine, galanthamine and the like.

Examples of the erectile dysfunction improving drug include apomorphine,sildenafil citrate and the like.

Examples of the therapeutic agents for pollakisuria or anischuriainclude flavoxate hydrochloride, oxybutynin hydrochloride, propiverinehydrochloride and the like.

Examples of the therapeutic agents for dysuria include acetylcholineesterase inhibitors (e.g., distigmine) and the like.

Furthermore, drugs having a cachexia-improving action established inanimal models and clinical situations, such as cyclooxygenase inhibitors(e.g., indomethacin), progesterone derivatives (e.g., megestrolacetate), glucosteroids (e.g., dexamethasone), metoclopramide agents,tetrahydrocannabinol agents, fat metabolism improving agents (e.g.,eicosapentanoic acid), growth hormones, IGF-1, or antibodies to acachexia-inducing factor such as TNF-α, LIF, IL-6, oncostatin M and thelike, can be used in combination with the compound of the presentinvention.

Furthermore, glycosylation inhibitors (e.g., ALT-711), nerveregeneration promoting drugs (e.g., Y-128, VX853, prosaptide),antidepressants (e.g., desipramine, amitriptyline, imipramine),antiepileptics (e.g., lamotrigine, Trileptal, Keppra, Zonegran,Pregabalin, Harkoseride, carbamazepine), antiarrhythmic agents (e.g.,mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelinreceptor antagonists (e.g., ABT-627), monoamine uptake inhibitors (e.g.,tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonists(e.g., gabapentin, gabapentin MR agent), α₂ receptor agonists (e.g.,clonidine), local analgesics (e.g., capsaicin), antianxiety drugs (e.g.,benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil),dopamine receptor agonists (e.g., apomorphine), midazolam, Ketoconazoleand the like can also be used in combination with the compound of thepresent invention.

The concomitant drug is preferably an insulin preparation, an insulinsensitizer (preferably pioglitazone or its hydrochloride), anα-glucosidase inhibitor (preferably voglibose), a biguanide (preferablymetformin or hydrochloride thereof), a sulfonylurea (preferablyglibenclamide, glimepiride), mitiglinide or calcium salt hydratethereof, nateglinide, a dipeptidyl peptidase IV inhibitor (preferablyalogliptin or benzoate thereof, trelagliptin or succinate thereof),SGLT2 inhibitor, GLP-1 receptor agonist and the like. For enhancing thefood ingestion suppressive action, a combined use with a dipeptidylpeptidase IV inhibitor (preferably, alogliptin or a salt thereof) ismore preferable. Two or more kinds of the above-mentioned concomitantdrugs may be used in combination at an appropriate ratio.

When the compound of the present invention is used in combination with aconcomitant drug, the amounts thereof can be increased or decreasedwithin the safe range in consideration of the counter effect thereof.Particularly, the doses of insulin sensitizer, dipeptidyl peptidase IVinhibitor, α-glucosidase inhibitor, biguanide, insulin secretagogue,SGLT2 inhibitor and GLP-1 receptor agonist can be reduced from thegeneral doses. Therefore, the counter effects that will be caused bythese agents can be prevented safely. In addition, the doses oftherapeutic agents for diabetic complications, therapeutic agents forhyperlipidemia, and antihypertensive agents can be reduced and, as aresult, the counter effects that will be caused by these agents can beprevented effectively.

By combining the compound of the present invention with a concomitantdrug, superior effects such as

(1) decreasable dose of the compound of the present invention or aconcomitant drug as compared to single administration of the compound ofthe present invention or a concomitant drug,(2) possible setting of a long treatment period by selecting aconcomitant drug having different action and mechanism from those of thecompound of the present invention,(3) possible designing of a sustained treatment effect by selecting aconcomitant drug having different action and mechanism from those of thecompound of the present invention,(4) a synergistic effect possibly afforded by a combined use of thecompound of the present invention and a concomitant drug, and the likemay be achieved.

When the compound of the present invention and a concomitant drug areused in combination, the administration time of the compound of thepresent invention and the concomitant drug is not restricted, and thecompound of the present invention and the concomitant drug may beadministered simultaneously, or may be administered at staggered times,to an administration subject. The dosage of the concomitant drug may bedetermined according to the dose clinically used, and can beappropriately selected depending on an administration subject,administration route, disease, combination and the like.

As the administration mode of the compound of the present invention andthe concomitant drug, the following methods can be mentioned: (1) Thecompound of the present invention and the concomitant drug aresimultaneously formulated to give a single preparation which isadministered. (2) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered simultaneously by the sameadministration route. (3) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered by the same administration route atstaggered times. (4) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered simultaneously by the differentadministration routes. (5) The compound of the present invention and theconcomitant drug are separately formulated to give two kinds ofpreparations which are administered by the different administrationroutes at staggered times (e.g., the compound of the present inventionand the concomitant drug are administered in this order, or in thereverse order), and the like.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and the presentinvention can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for a mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

Elution in column chromatography in the Examples was performed underobservation by TLC (Thin Layer Chromatography, thin layerchromatography) unless otherwise specified. In the observation by TLC,60 F₂₅₄ manufactured by Merck was used as a TLC plate and the solventused as an elution solvent in the column chromatography was used as aneluent. For detection, a UV detector was adopted. In silica gel columnchromatography, the indication of NH means use ofaminopropylsilane-bonded silica gel, and the indication of Diol meansuse of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. Inpreparative HPLC (high performance liquid chromatography), theindication of C18 means use of octadecyl-bonded silica gel. The ratio ofelution solvents is, unless otherwise specified, a volume mixing ratio.

For the analysis of ¹H NMR, ACD/SpecManager (trade name) software andthe like were used. Very mild peaks for protons of a hydroxy group, anamino group and the like may not be described.

MS was measured by LC/MS. As ionization method, ESI method or APCImethod was used. The data indicates those found. Generally, molecularion peaks are observed but may sometimes be observed as a fragment ion.In the case of a salt, generally, a molecular ion-peak or a fragment ionpeak of a free form is observed.

The unit of sample concentration (c) in optical rotation ([α]_(D)) isg/100 mL.

The elemental analytical value (Anal.) is shown by Calculated value(Calcd) and measured value (Found).

The peak in the powder X-ray diffraction in the Examples means a peakmeasured by Ultima IV (Rigaku Corporation, Japan) at room temperatureusing Cu Kα radiation as a radiation source. The measurement conditionswere as follows.

Electric pressure/Electric current: 40 kV/50 mA

Scan speed: 6 degree/min

Scan range of 2 Theta: 2-35 degree

The crystallinity by powder X-ray diffraction in the Examples wascalculated by the Hermans method.

In Examples, the following abbreviations are used.

mp: melting pointMS: mass spectrumM: mol concentrationN: normalityCDCl₃: deuterochloroformDMSO-d₆: deuterodimethyl sulfoxide¹H NMR: proton nuclear magnetic resonanceLC/MS: liquid chromatograph mass spectrometerESI: electrospray ionizationAPCI: atomospheric pressure chemical ionizationSFC: supercritical fluid chromatographyTFA: trifluoroacetic acidIPE: diisopropyl ether

DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide

THF: tetrahydrofuranDME: 1,2-dimethoxyethaneMeOH: methanolEtOH: ethanolDMSO: dimethyl sulfoxideNMP: 1-methylpyrrolidin-2-oneTEA: triethylamineEt₂O: diethyl etherBINAP: 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)

Example 1(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid A) 1-(2-(benzyloxy)-5-(methoxymethoxy)pyridin-4-yl)ethanone

To a mixture of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (43.93 g) andTHE (400 mL) was added n-butyllithium (1.6 N hexane solution, 146 mL) at−78° C. The mixture was stirred under a nitrogen atmosphere at the sametemperature for 1 hr, and N-methoxy-N-methylacetamide (36.9 g) wasadded. The mixture was stirred under a nitrogen atmosphere at −78° C.for 2 hr. To the mixture was added at 0° C. saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (30.03g). MS: [M+H]⁺ 288.0.

B)1-(2-(benzyloxy)-5-(methoxymethoxy)pyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one

A mixture of 1-(2-(benzyloxy)-5-(methoxymethoxy)pyridin-4-yl)ethanone(23.0 g) and N,N-dimethylformamide dimethyl acetal (130 g) was stirredat 100° C. overnight, and the reaction mixture was concentrated. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (25.38 g). MS: [M+H]⁺ 343.2.

C) 6-(benzyloxy)-4H-pyrano[2,3-c]pyridin-4-one

To a mixture of1-(2-(benzyloxy)-5-(methoxymethoxy)pyridin-4-yl)-3-(dimethylamino)prop-2-en-1-one(31.8 g) and THE (300 mL) was added 6N hydrochloric acid (155 mL) atroom temperature. The mixture was stirred under a nitrogen atmosphere atthe same temperature for 2 hr, and the reaction mixture wasconcentrated. To the obtained residue was added water, and the mixturewas stirred at room temperature for 30 min. The obtained precipitate wascollected by filtration, washed with water and dried under reducedpressure to give the title compound (21.18 g). MS: [M+H]⁺ 254.0.

D) 6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ol

To a mixture of 6-(benzyloxy)-4H-pyrano[2,3-c]pyridin-4-one (13.4 g) andMeOH (400 mL) were added nickel(II) chloride (6.86 g) and sodiumborohydride (6.01 g) at room temperature. The mixture was stirred at thesame temperature for 3 hr. To the mixture was added at 0° C. saturatedaqueous ammonium chloride solution, and the mixture was concentratedunder reduced pressure. The residue was extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the title compound (11.0 g). MS: [M+H]⁺ 258.1.

E) 6-(benzyloxy)-2,3-dihydro-4H-pyrano[2,3-c]pyridin-4-one

To a mixture of 6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ol(11 g), TEA (19.47 g) and DMSO (250 mL) was added sulfurtrioxide-pyridine complex (20.41 g) at room temperature. The mixture wasstirred at room temperature for hr. To the mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer wasseparated, washed successively with 1N hydrochloric acid, saturatedaqueous sodium hydrogen carbonate solution, water and saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was washed with IPE to give the title compound(8.21 g). MS: 256.1.

F) ethyl(6-(benzyloxy)-2,3-dihydro-4H-pyrano[2,3-c]pyridine-4-ylidene)acetate

To a mixture of ethyl (diethoxyphosphoryl)acetate (17.67 g) and THE (150mL) was added sodium hydride (60% in oil, 2.52 g) at 0° C. The mixturewas stirred at the same temperature for 30 min. To the mixture was addeda solution of 6-(benzyloxy)-2,3-dihydro-4H-pyrano[2,3-c]pyridin-4-one(8.05 g) in THE (50 mL). The mixture was stirred under a nitrogenatmosphere at room temperature for 2 hr. To the mixture was added 1Nhydrochloric acid at 0° C., and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (8.46g). MS: [M+H]⁺ 326.1.

G) ethyl (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

To a mixture of ethyl(6-(benzyloxy)-2,3-dihydro-4H-pyrano[2,3-c]pyridine-4-ylidene)acetate(450 mg) and MeOH (8 mL) were added nickel(II) chloride (179 mg) andsodium borohydride (157 mg) at room temperature. The mixture was stirredat the same temperature for 2 hr. To the mixture was added sodiumborohydride (157 mg) at room temperature. The mixture was stirred at thesame temperature for 15 hr. To the mixture was added at 0° C. saturatedaqueous ammonium chloride solution, and the mixture was extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the title compound (340 mg). MS: [M+H]⁺ 328.1.

H) ethyl (6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

A mixture of ethyl(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (0.5028g) and TFA (3 mL) was stirred 60° C. for 6 hr, and the reaction mixturewas concentrated. To the obtained residue was added IPE, and theprecipitate was collected by filtration and washed with IPE to give thetitle compound (0.2812 g). MS: [M+H]⁺ 238.0.

I) 2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxybenzaldehyde

A mixture of 2-fluoro-4-methoxybenzaldehyde (5 g),piperidin-4-ylmethanol (4.48 g), potassium carbonate (8.97 g), and DMSO(50 mL) was stirred under a nitrogen atmosphere at 120° C. for 1 hr. Tothe mixture was added water at room temperature, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (7.55 g). ¹H NMR (400 MHz, DMSO-d₆) δ1.37 (2H, q, J=11.8Hz), 1.45-1.59 (1H, m), 1.77 (2H, d, J=12.4 Hz), 2.81 (2H, t, J=11.8Hz), 3.26 (2H, d, J=11.4 Hz), 3.31-3.37 (2H, m), 3.83 (3H, s), 4.45-4.53(1H, m), 6.61 (1H, s), 6.67 (1H, d, J=8.7 Hz), 7.66 (1H, d, J=8.4 Hz),9.99 (1H, s).

J) 4-methoxy-2-(4-((methoxymethoxy)methyl)piperidin-1-yl)benzaldehyde

To a mixture of2-(4-(hydroxymethyl)piperidin-1-yl)-4-methoxybenzaldehyde (4.99 g),DIPEA (10.35 g), and THE (50 mL) was-added chloromethyl methyl ether(4.83 g) at room temperature. The mixture was stirred at the sametemperature for 5 hr. The mixture was added to water, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (5.2491 g). MS: [M+H]⁺ 294.2.

K) 4-((methoxymethoxy)methyl)-1-(5-methoxy-2-vinylphenyl)piperidine

To a mixture of methyl(triphenyl)phosphonium iodide (4.76 g) and THE (20mL) was added potassium tert-butoxide (1.101 g) at 0° C. The mixture wasstirred at room temperature for 1 hr. To the mixture was added asolution of4-methoxy-2-(4-((methoxymethoxy)methyl)piperidin-1-yl)benzaldehyde(1.1515 g) in THE at 0° C. The mixture was stirred at room temperaturefor 2 hr. To the mixture was added a saturated aqueous ammonium chloridesolution at 0° C., and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.0777 g). MS: [M+H]⁺ 292.2.

L)4-((methoxymethoxy)methyl)-1-(5-methoxy-2-((1E)-3,3,3-trifluoroprop-1-en-1-yl)phenyl)piperidine

To a mixture of 1-trifluoromethyl-1,2-benzoiodoxol-3(1H)-one (1.266 g)and tetrakis(acetonitrile)copper(I) hexafluorophosphate (0.249 g) wasadded a solution of4-((methoxymethoxy)methyl)-1-(5-methoxy-2-vinylphenyl)piperidine (0.9731g) in dichloromethane (20 mL) at room temperature. The mixture wasstirred at the same temperature for 2 hr. The mixture was added to asaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.3373 g). MS: [M+H]⁺ 360.2.

M)4-((methoxymethoxy)methyl)-1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidine

A mixture of4-((methoxymethoxy)methyl)-1-(5-methoxy-2-((1E)-3,3,3-trifluoroprop-1-en-1-yl)phenyl)piperidine(0.2888 g), 10% palladium carbon (0.05 g) and EtOH (7 mL) was stirred atnormal pressure under a hydrogen atmosphere at 50° C. for 2 hr. Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure to give the title compound (0.2668 g). MS: [M+H]⁺362.2.

N) (1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methanol

To a mixture of4-((methoxymethoxy)methyl)-1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidine(0.1696 g) and MeOH (7 mL) was added 6N hydrochloric acid (1 mL) at roomtemperature. The mixture was stirred at 60° C. for 3 hr. The mixture wasneutralized with 1N aqueous sodium hydroxide solution and extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.1468g). MS: [M+H]⁺ 318.1.

O) ethyl(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

A mixture of(1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methanol(0.1395 g), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (0.125 g),(tributylphosphoranylidene)acetonitrile (0.318 g) and toluene (8 mL) wasstirred at 100° C. for 3 hr. The mixture was added to water, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.1622 g). MS: [M+H]⁺ 537.4.

P)(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid

To a mixture of ethyl(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(0.072 g), THE (2 mL) and MeOH (2.000 mL) was added 1N aqueous sodiumhydroxide solution (1.5 mL) at room temperature. The mixture was stirredat room temperature overnight. The mixture was neutralized with 1Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (0.0587 g). ¹H NMR (300 MHz, CDCl₃)δ1.43-1.59 (2H, m), 1.81-1.98 (4H, m), 2.14-2.26 (1H, m), 2.30-2.48 (2H,m), 2.53-2.74 (3H, m), 2.77-2.93 (3H, m), 3.00-3.10 (2H, m), 3.30-3.40(1H, m), 3.78 (3H, s), 4.10-4.25 (4H, m), 6.55 (1H, s), 6.58 (1H, dd,J=8.4, 2.6 Hz), 6.69 (1H, d, J=2.6 Hz), 7.06 (1H, d, J=8.4 Hz), 7.76(1H, s).

Example 2(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid A) 2-(benzyloxy)-4-bromo-5-(methoxymethoxy)pyridine

To a mixture of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (3.0295 g) andTHE (60 mL) was added n-butyllithium (1.6 M hexane solution, 11.58 mL)at −78° C. The mixture was stirred at the same temperature for 1 hr.1,2-Dibromo-1,1,2,2-tetrafluoroethane (16.05 g) was added to the mixtureat −78° C. The mixture was stirred at the same temperature for 2 hr. Themixture was added to a saturated aqueous sodium thiosulfate solution,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (2.6277 g). MS: [M+H]⁺ 324.0.

B) 6-(benzyloxy)-4-bromopyridin-3-ol

To a mixture of 2-(benzyloxy)-4-bromo-5-(methoxymethoxy)pyridine (0.8015g) and THF (12 mL) was added 6N hydrochloric acid (6 mL) at roomtemperature. The mixture was stirred at the same temperature for 6 hr.The mixture was added to water, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.5957 g). MS: [M+H]⁺280.0.

C) 2-(benzyloxy)-4-bromo-5-(2,2,3,3,3-pentafluoropropoxy)pyridine

A mixture of 6-(benzyloxy)-4-bromopyridin-3-ol (0.5751 g),2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (1.158 g), cesiumcarbonate (2.007 g) and DMF (10 mL) was stirred at room temperatureovernight. The mixture was added to water, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.8111g). MS: [M+H]⁺ 412.0.

D) 4-bromo-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2(1H)-one

A mixture of2-(benzyloxy)-4-bromo-5-(2,2,3,3,3-pentafluoropropoxy)pyridine (3.1445g) and TEA (30 mL) was stirred at 60° C. for 5 hr, and the reactionmixture was concentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.3711g). MS: [M+H]⁺ 322.0.

E) 4-bromo-2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridine

A mixture of 4-bromo-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-2(1H)-one(2.3711 g), silver(I) carbonate (3.05 g), methyl iodide (4.58 mL) andtoluene (100 mL) was stirred at 60° C. for 3 hr. The mixture wasfiltered and the filtrate was concentrated. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.9217 g). MS: [M+H]⁺ 336.0.

F) ethyl1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidine-4-carboxylate

A mixture of 4-bromo-2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridine(0.9233 g), ethyl piperidine-4-carboxylate (0.648 g),2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.216 g),tris(dibenzylideneacetone)dipalladium(0) (0.126 g), tripotassiumphosphate (1.750 g), and DME (15 mL) was subjected to microwaveirradiation at 130° C. for 3 hr. The mixture was added to water, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.6721 g). MS: [M+H]⁺ 413.1.

G)(1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methanol

To a mixture of ethyl1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidine-4-carboxylate(0.6721 g) and THF (15 mL) was added lithium borohydride (0.107 g) atroom temperature. The mixture was stirred at 60° C. for 3 hr. To themixture was added saturated aqueous ammonium chloride solution at 0° C.,and the mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.5358 g). MS: [M+H]⁺ 371.1.

H) ethyl(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

A mixture of(1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methanol(0.1972 g), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (0.152 g),(tributylphosphoranylidene)acetonitrile (0.386 g), and toluene (10 mL)was stirred at 100° C. for 3 hr. The mixture was added to water, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.2310 g). MS: [M+H]⁺ 590.4.

I)(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid

To a mixture of ethyl(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(0.0278 g), THE (1.5 mL) and MeOH (1.500 mL) was added 1N aqueous sodiumhydroxide solution (0.6 mL) at room temperature. The mixture was stirredat the same temperature overnight. The mixture was neutralized with 1Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (0.0184 g). H NMR (300 MHz, CDCl₃) δ1.40-1.55 (2H, m), 1.81-2.01 (4H, m), 2.13-2.25 (1H, m), 2.52-2.75 (3H,m), 2.87 (1H, dd, J=16.3, 4.7 Hz), 3.28-3.40 (1H, m), 3.64-3.75 (2H, m),3.87 (3H, s), 4.08-4.25 (4H, m), 4.31-4.43 (2H, m), 6.19 (1H, s), 6.54(1H, s), 7.70 (1H, s), 7.74 (1H, s).

Example 3(3-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)aceticacid A) ethyl 5-(3-butoxy-3-oxoprop-1-en-1-yl)-2-methoxyisonicotinate

A mixture of ethyl 5-bromo-2-methoxyisonicotinate (11.73 g),palladium(II) acetate (1.012 g), tri-tert-butylphosphoniumtetrafluoroborate (3.93 g), butyl acrylate (28.9 g), DIPEA (17.49 g) andNMP (30 mL) was stirred under a nitrogen atmosphere at 120° C. for 15hr. To the mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was separated, washed successively withwater and saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (13.3 g). MS: [M+H]⁺ 308.1.

B) ethyl 5-(3-butoxy-3-oxopropyl)-2-methoxyisonicotinate

A mixture of ethyl5-(3-butoxy-3-oxoprop-1-en-1-yl)-2-methoxyisonicotinate (7.54 g), 10%palladium carbon (containing 55% water, 3 g) and THF (300 mL) wasstirred at normal pressure under a hydrogen atmosphere at roomtemperature for 15 hr. The catalyst was filtered off and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (7.08 g). MS: [M+H]⁺ 310.1.

C) butyl3-methoxy-5-oxo-6,7-dihydro-5H-cyclopenta[c]pyridine-6-carboxylate

To a mixture of ethyl 5-(3-butoxy-3-oxopropyl)-2-methoxyisonicotinate(10.8 g) and THE (500 mL) was added sodium hydride (60% in oil, 1.676 g)at 0° C. The mixture was stirred at 60° C. for 20 hr. To the mixture wasadded 0.5N hydrochloric acid (100 mL) at 0° C. To the mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed successively with water and saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (7.49 g). The obtainedcompound was used for the next step without further purification.

D) 3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one

A mixture of butyl3-methoxy-5-oxo-6,7-dihydro-5H-cyclopenta[c]pyridine-6-carboxylate (7.76g), DMSO (180 mL) and water (20 mL) was stirred at 150° C. for 1 hr. Themixture was cooled to room temperature, water was added, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed successively with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (4.44 g). MS: [M+H]⁺ 164.0.

E) ethyl(3-methoxy-6,7=dihydro-5H-cyclopenta[c]pyridin-5-ylidene)acetate

To a mixture of sodium hydride (60% in oil, 1.405 g) and toluene (150mL) was added ethyl (diethoxyphosphoryl)acetate (7.87 g) at 0° C. Themixture was stirred at 0° C. for 30 min and a solution of3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-one (3.82 g) in toluene(30 mL) was added. The mixture was stirred at room temperature for 15hr. To the mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (4.67g) as an E/Z mixture. The obtained compound was used in the next stepwithout purification.

F) ethyl (3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate

A mixture of ethyl(3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ylidene)acetate (E/Zmixture) (4.67 g), 10% palladium carbon (2 g) and THF (200 mL) wasstirred at normal pressure under a hydrogen atmosphere at roomtemperature for 3 hr. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (4.46 g). MS: [M+H]⁺ 236.1.

G) ethyl (3-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate

A mixture of ethyl(3-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate (2.47 g),pyridine hydrochloride (12.13 g) and DMF (20 mL) was stirred at 120° C.for 2.5 hr, and the reaction mixture was concentrated. To the residuewas added toluene and the mixture was concentrated. The residue wasneutralized with saturated aqueous sodium hydrogen carbonate solutionand concentrated under reduced pressure. To the obtained solid was addedTHF (100 mL) and the mixture was stirred at room temperature for 30 min.The mixture was filtered and the filtrate was concentrated. The residuewas purified by silica gel column chromatography (ethyl acetate/MeOH) togive the title compound (2.04 g). MS: [M+H]+ 222.1.

H) ethyl(3-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate

A mixture of(1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methanol(0.0296 g), ethyl(3-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate (0.027 g),(tributylphosphoranylidene)acetonitrile (0.058 g) and toluene (3 mL) wasstirred at 100° C. overnight. The mixture was added to water, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.0295 g). MS: [M+H]⁺ 574.4.

I)(3-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)aceticacid

To a mixture of ethyl(3-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate(0.0295 g), THE (1.5 mL) and MeOH (1.500 mL) was added 1N aqueous sodiumhydroxide solution (0.6 mL) at room temperature. The mixture was stirredat the same temperature overnight. The mixture was neutralized with 1Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (0.0241 g). ¹H NMR (300 MHz, CDCl₃)δ1.41-1.58 (2H, m), 1.70-1.87 (1H, m), 1.89-2.06 (3H, m), 2.38-2.58 (2H,m), 2.63-2.96 (5H, m), 3.47-3.60 (1H, m), 3.66-3.76 (2H, m), 3.87 (3H,s), 4.16 (2H, d, J=6.3 Hz), 4.31-4.43 (2H, m), 6.20 (1H, s), 6.60 (1H,s), 7.70 (1H, s), 7.98 (1H, d, J=0.8 Hz).

Example 4(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)aceticacid A) ethyl 1-(2-bromo-5-methoxyphenyl)piperidine-4-carboxylate

A mixture of 1-bromo-2-iodo-4-methoxybenzene (15.03 g), ethylpiperidine-4-carboxylate (8.31 g), palladium(II) acetate (0.539 g),BINAP (1.794 g), cesium carbonate (23.47 g) and xylene (150 mL) wasstirred under an argon atmosphere at 130° C. overnight and at 100° C.for 20 hr. The reaction mixture was filtered and the filtrate wasconcentrated. To the residue was added water at room temperature and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with aqueous citric acid solution and saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (4.38 g). ¹H NMR (300MHz, CDCl₃) δ1.28 (3H, t, J=7.1 Hz), 1.90-2.08 (4H, m), 2.43 (1H, tt,J=10.2, 5.1 Hz), 2.60-2.74 (2H, m), 3.35 (2H, dt, J=11.8, 3.1 Hz), 3.78(3H, s), 4.17 (2H, q, J=7.1 Hz), 6.46 (1H, dd, J=8.7, 2.9 Hz), 6.59 (1H,d, J=2.9 Hz), 7.43 (1H, d, J=8.7 Hz).

B) tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of ethyl 1-(2-bromo-5-methoxyphenyl)piperidine-4-carboxylate(1.507 g),(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (2g), [1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride(0.322 g), 2 M aqueous sodium carbonate solution (4.84 mL) and DMF (30mL) was stirred under a nitrogen atmosphere at 100° C. for 2 hr. To themixture was added water at room temperature and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.63 g). ¹H NMR (300 MHz, CDCl₃) δ1.27 (3H, t, J=7.1Hz), 1.50 (9H, s), 1.69-1.87 (2H, m), 1.91-2.02 (2H, m), 2.36 (1H, tt,J=11.2, 4.0 Hz), 2.52-2.68 (4H, m), 3.32 (2H, d, J=12.0 Hz), 3.59 (2H,t, J=5.6 Hz), 3.79 (3H, s), 4.03 (2H, d, J=2.5 Hz), 4.15 (2H, q, J=7.2Hz), 5.68 (1H, s), 6.47-6.58 (2H, m), 7.01 (1H, d, J=8.1 Hz).

C) tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(1.63 g), 10% palladium carbon (800 mg) and THE (50 mL) was stirred atnormal pressure under a hydrogen atmosphere at room temperatureovernight. The catalyst was filtered off and the filtrate wasconcentrated under reduced pressure to give the title compound (1.57 g).H NMR (300 MHz, CDCl₃) δ1.25-1.32 (3H, m), 1.49 (9H, s), 1.48-1.63 (2H,m), 1.64-1.75 (2H, m), 1.79-2.08 (4H, m), 2.32-2.50 (1H, m), 2.68 (2H,td, J=11.4, 2.5 Hz), 2.79 (2H, t, J=12.3 Hz), 2.96-3.16 (3H, m), 3.78(3H, s), 4.07-4.32 (4H, m), 6.58-6.67 (2H, m), 7.08 (1H, d, J=8.3 Hz).

D) ethyl1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidine-4-carboxylate

To a mixture of tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)piperidine-1-carboxylate(518 mg) and EtOAc (3 mL) was added 4N hydrogen chloride ethyl acetatesolution (4 mL) at room temperature. The mixture was stirred under anitrogen atmosphere at room temperature for 20 min and the reactionmixture was concentrated. To a mixture of the obtained residue, TEA(1174 mg) and acetonitrile (5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (1346 mg) at room temperature. The mixture wasstirred under a nitrogen atmosphere at 60° C. for 20 min, and thereaction mixture was concentrated. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (448.2 mg). ¹H NMR (400 MHz, CDCl₃) δ1.29 (3H, t, J=6.7 Hz),1.63-1.82 (4H, m), 1.89 (2H, q, J=11.9 Hz), 1.97-2.06 (2H, m), 2.34-2.52(3H, m), 2.67 (2H, t, J=11.4 Hz), 2.88-3.15 (7H, m), 3.78 (3H, s),4.15-4.24 (2H, m), 6.60-6.67 (2H, m), 7.16 (1H, d, J=8.0 Hz).

E)(1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol

To a mixture of lithium aluminum hydride (161 mg) and Et₂O (5 mL) wasadded a solution of ethyl1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidine-4-carboxylate(604.9 mg) in diethyl ether at 0° C. The mixture was stirred under anitrogen atmosphere at 0° C. for 20 min. To the mixture were added waterand aqueous sodium hydroxide solution, and the obtained precipitate wasremoved by filtration. The filtrate was concentrated under reducedpressure to give the title compound (527.4 mg). ¹H NMR (300 MHz,DMSO-d₆) δ1.22-1.37 (2H, m), 1.38-1.53 (1H, m), 1.53-1.70 (4H, m), 1.75(2H, d, J=12.4 Hz), 2.40 (2H, td, J=10.7, 3.9 Hz), 2.53-2.64 (2H, m),2.75-2.96 (3H, m), 3.02 (2H, d, J=11.5 Hz), 3.17 (2H, q, J=10.3 Hz),3.29-3.34 (2H, m), 3.70 (3H, s), 4.45 (1H, t, J=5.3 Hz), 6.54-6.64 (2H,m), 7.12 (1H, d, J=9.2 Hz).

F) ethyl(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate

To a mixture of(1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol(178 mg), ethyl(3-hydroxy-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate (102 mg) andtoluene (3 mL) was added (tributylphosphoranylidene)acetonitrile (222mg) at room temperature. The mixture was stirred under a nitrogenatmosphere at 100° C. for 3 hr. The mixture was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give the title compound(174.9 mg). H NMR (300 MHz, CDCl₃) δ1.28 (3H, t, J=7.2 Hz), 1.41-1.60(2H, m), 1.65-1.84 (5H, m), 1.86-2.02 (3H, m), 2.32-2.53 (4H, m),2.61-3.16 (12H, m), 3.43-3.59 (1H, m), 3.78 (3H, s), 4.07-4.25 (4H, m),6.58 (1H, s), 6.62 (1H, dd, J=8.5, 2.6 Hz), 6.67 (1H, d, J=2.6 Hz), 7.15(1H, d, J=8.5 Hz), 7.97 (1H, d, J=0.8 Hz).

G)(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)aceticacid

To a mixture of ethyl(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate(39 mg), THF (1 mL) and MeOH (0.500 mL) was added 1N aqueous sodiumhydroxide solution (1 mL) at room temperature. The mixture was stirredat 60° C. for 30 min. The mixture was neutralized with 1N hydrochloricacid at room temperature and extracted with ethyl acetate. The organiclayer was separated, washed with water and saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained solid was crystallized from ethyl acetate/hexane to give thetitle compound (28 mg). ¹H NMR (300 MHz, DMSO-d₆) δ1.35-1.52 (2H, m),1.53-1.75 (4H, m), 1.77-1.96 (3H, m), 2.22-2.47 (4H, m), 2.63 (2H, t,J=11.0 Hz), 2.70-3.08 (8H, m), 3.17 (2H, q, J=10.3 Hz), 3.29-3.46 (2H,m), 3.70 (3H, s), 4.14 (2H, d, J=6.2 Hz), 6.56-6.65 (2H, m), 6.68 (1H,s), 7.13 (1H, d, J=9.0 Hz), 7.96 (1H, s), 12.35 (1H, brs).

Example 5(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid A) tert-butyl4-(((4-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)oxy)methyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.005g), ethyl (6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(1.7 g), (tributylphosphoranylidene)acetonitrile (3.46 g) and toluene(20 mL) was stirred at 100° C. overnight. The reaction mixture was addedto water, and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (2.36 g). MS: [M+H]⁺ 435.2.

B) ethyl(6-(piperidin-4-ylmethoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

To a mixture of tert-butyl4-(((4-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)oxy)methyl)piperidine-1-carboxylate(0.4104 g) and toluene (5 mL) was added TEA (3 mL) at room temperature,and the mixture was stirred at the same temperature for 1 hr. Thereaction mixture was concentrated, and the residue was diluted withethyl acetate. Saturated aqueous sodium hydrogen carbonate solution wasadded and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to give thetitle compound (0.3324 g). MS: [M+H]⁺ 335.2.

C) ethyl(6-((1-(5-bromo-2-methoxypyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

A mixture of 5-bromo-4-chloro-2-methoxypyridine (416 mg), ethyl(6-(piperidin-4-ylmethoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(938 mg), potassium carbonate (775 mg) and DMSO (10 mL) was stirred at100° C. for 40 hr. The reaction mixture was added to water, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed successively with water and saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (396.0 mg). MS: [M+H]⁺520.1.

D) tert-butyl4-(4-(((4-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)oxy)methyl)piperidin-1-yl)-6-methoxy-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate

A mixture of ethyl(6-((1-(5-bromo-2-methoxypyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(396.0 mg), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(353 mg), 2 M aqueous sodium carbonate solution (0.761 mL),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane adduct (62.1 mg) and DME (2.5 mL) was subjected tomicrowave irradiation at 130° C. for 40 min under a nitrogen atmosphere.The reaction mixture was added to water, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed successivelywith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (379.3 mg). MS: [M+H]⁺ 623.2.

E) tert-butyl4-(4-(4-(((4-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)oxy)methyl)piperidin-1-yl)-6-methoxypyridin-3-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(4-(((4-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)oxy)methyl)piperidin-1-yl)-6-methoxy-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate(379.3 mg), 10% palladium carbon (64.8 mg) and EtOH (4 mL) was stirredat normal pressure under a hydrogen atmosphere at room temperatureovernight and at 50° C. for 1.5 hr. The catalyst was filtered off andthe filtrate was concentrated under reduced pressure to give the titlecompound. The obtained compound was used for the next step withoutfurther purification. MS: [M+H]⁺ 625.2.

F) ethyl(6-((1-(2-methoxy-5-(piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetatehydrochloride

A mixture of tert-butyl4-(4-(4-(((4-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)oxy)methyl)piperidin-1-yl)-6-methoxypyridin-3-yl)piperidine-1-carboxylateobtained in step (E) and 4 M hydrogen chloride ethyl acetate solution(0.5 mL) was stirred at room temperature for 4 hr, and the reactionmixture was concentrated to give the title compound. The obtainedcompound was used for the next step without further purification.

G) ethyl(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

A mixture of ethyl(6-((1-(2-methoxy-5-(piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetatehydrochloride obtained in step (F), 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.175 mL), potassium carbonate (253 mg) andDMF (3 mL) was stirred at 80° C. for 4 hr. The reaction mixture wasadded to water, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was separated by silica gel columnchromatography (ethyl acetate/hexane) and then HPLC (C18, mobilephase:water/acetonitrile (containing 0.1% TFA)), to the obtainedfraction was added saturated aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate. The extract was driedover anhydrous magnesium sulfate and concentrated under reduced pressureto give the title compound (175.3 mg). MS: [M+H]⁺ 607.2.

H)(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid

To a mixture of ethyl(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(175.3 mg), EtOH (1.000 mL) and THE (1 mL) was added 2N aqueous sodiumhydroxide solution (0.5 mL) at room temperature. The mixture was stirredat room temperature for 3 hr and concentrated under reduced pressure. Tothe residue was added water and the mixture was neutralized with 2Nhydrochloric acid and the obtained solid was collected to give the titlecompound (142.6 mg). ¹H NMR (300 MHz, DMSO-d₆) δ1.31-1.52 (2H, m),1.58-1.93 (8H, m), 1.96-2.11 (1H, m), 2.32-2.70 (6H, m), 2.81 (1H, dd,J=16.2, 5.0 Hz), 2.97-3.27 (7H, m), 3.78 (3H, s), 4.00-4.22 (4H, m),6.31 (1H, s), 6.70 (1H, s), 7.66 (1H, s), 7.93 (1H, s), 12.35 (1H, s).

Example 6(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

A racemate (120 mg) of(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid was separated by SFC (column: CHIRALPAK IA (trade name), 20 mmID×250 mm L, manufactured by Daicel Corporation, mobile phase: carbondioxide/methanol=660/340) and the title compound (37.1 mg) with smallerretention time was obtained. ¹H NMR (300 MHz, CDCl₃) δ1.41-1.63 (2H, m),1.69-2.03 (8H, m), 2.17-2.27 (1H, m), 2.39-2.74 (6H, m), 2.87 (1H, dd,J=16.1, 4.6 Hz), 2.98-3.22 (6H, m), 3.28-3.44 (1H, m), 3.90 (3H, s),4.06-4.27 (4H, m), 6.31 (1H, s), 6.58 (1H, s), 7.76 (1H, s), 7.96 (1H,s).

Example 7(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

A racemate (120 mg) of(6-((1-(2-methoxy-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid was separated by SFC (column:CHIRALPAK IA (trade name), 20 mmID×250 mm L, manufactured by Daicel Corporation, mobile phase: carbondioxide/methanol=660/340) and the title compound (32.7 mg) with longerretention time was obtained. ¹H NMR (300 MHz, CDCl₃) δ1.42-1.62 (2H, m),1.70-2.01 (8H, m), 2.21 (1H, brs), 2.38-2.76 (6H, m), 2.87 (1H, dd,J=16.1, 4.5 Hz), 2.98-3.22 (6H, m), 3.37 (1H, dd, J=9.1, 4.8 Hz), 3.90(3H, s), 4.11-4.28 (4H, m), 6.31 (1H, s), 6.58 (1H, s), 7.76 (1H, s),7.96 (1H, s).

Example 8(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (0.0752 g) which is an optical isomer having longerretention time and obtained by separating a racemate of ethyl(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetateby SFC (column: CHIRALCEL OJH (trade name), 20 mm ID×250 mm L,manufactured by Daicel Corporation, mobile phase: carbondioxide/MeOH=880/120), THE (2.5 mL) and MeOH (2.500 mL) was added 1Naqueous sodium hydroxide solution (1.5 mL) at room temperature. Themixture was stirred at the same temperature overnight. The mixture wasneutralized with 1N hydrochloric acid and extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was suspended in a mixed solvent of IPE and hexane and theprecipitate was collected by filtration, washed with a mixed solvent ofIPE and hexane, and dried under reduced pressure to give the titlecompound (0.0676 g). ¹H NMR (300 MHz, CDCl₃) δ1.43-1.59 (2H, m),1.82-1.98 (4H, m), 2.14-2.27 (1H, m), 2.31-2.49 (2H, m), 2.54-2.74 (3H,m), 2.78-2.94 (3H, m), 3.01-3.10 (2H, m), 3.30-3.41 (1H, m), 3.78 (3H,s), 4.08-4.25 (4H, m), 6.55 (1H, s), 6.59 (1H, dd, J=8.3, 2.6 Hz), 6.69(1H, d, J=2.6 Hz), 7.06 (1H, d, J=8.3 Hz), 7.76 (1H, s).

Example 9(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer) A) ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

To a mixture of(1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol(266 mg), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (136 mg) andtoluene (3 mL) was added (tributylphosphoranylidene)acetonitrile (277mg) at room temperature. The mixture was stirred under a nitrogenatmosphere at 100° C. overnight and the reaction mixture wasconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (213.3mg). H NMR (300 MHz, CDCl₃) δ1.28 (3H, t, J=7.2 Hz), 1.40-1.58 (2H, m),1.62-2.00 (8H, m), 2.09-2.24 (1H, m), 2.38-2.58 (3H, m), 2.67 (2H, t,J=10.9 Hz), 2.80 (1H, dd, J=15.8, 4.9 Hz), 2.87-3.15 (7H, m), 3.28-3.41(1H, m), 3.78 (3H, s), 4.07-4.26 (6H, m), 6.54 (1H, s), 6.62 (1H, dd,J=8.4, 2.6 Hz), 6.67 (1H, d, J=2.6 Hz), 7.15 (1H, d, J=8.5 Hz), 7.75(1H, s).

B)(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(55.4 mg) which is an optical isomer having longer retention time andobtained by separating a racemate of ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetateby HPLC (column: CHIRALPAK IC (trade name), 50 mm ID×500 mm L,manufactured by Daicel Corporation, mobile phase:hexane/2-propanol=600/400), MeOH (1.000 mL) and THE (2 mL) was added 1Nsodium hydroxide (2 mL) at room temperature. The mixture was stirred at60° C. for 20 min. The mixture was neutralized with 1N hydrochloric acidat room temperature and extracted with ethyl acetate. The organic layerwas separated, washed with water and saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained solid was crystallized from ethyl acetate/hexane to give thetitle compound (42.8 mg). ¹H NMR (400 MHz, DMSO-d₆) δ1.30-1.49 (2H, m),1.54-1.71 (4H, m), 1.71-1.92 (4H, m), 1.95-2.12 (1H, m), 2.29-2.49 (3H,m), 2.63 (2H, t, J=11.5 Hz), 2.74-2.98 (4H, m), 3.02 (2H, d, J=10.9 Hz),3.11-3.25 (3H, m), 3.70 (3H, s), 3.99-4.23 (4H, m), 6.56-6.66 (2H, m),6.70 (1H, s), 7.13 (1H, d, J=7.7 Hz), 7.66 (1H, s), 12.35 (1H, brs).

Example 10(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate(61.6 mg) which is an optical isomer having shorter retention time andobtained by separating a racemate of ethyl(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetateby HPLC (column: CHIRALPAK IC (trade name), 50 mm ID×500 mm L,manufactured by Daicel Corporation, mobile phase:hexane/2-propanol=600/400), MeOH (1 mL) and THE (2 mL) was added 1Naqueous sodium hydroxide solution (2 mL) at room temperature. Themixture was stirred at 60° C. for 30 min. The mixture was neutralizedwith 1N hydrochloric acid at room temperature and extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The obtained residue was crystallized from ethylacetate/hexane to give the title compound (43.6 mg).

Example 11(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(0.1150 g) which is an optical isomer having longer retention time andobtained by separating a racemate of ethyl(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetateby SFC (column: CHIRALPAK IA (trade name), 20 mm ID×250 mm L,manufactured by Daicel Corporation, mobile phase: carbondioxide/MeOH=860/140), THE (3 mL) and MeOH (3.00 mL) was added 1Naqueous sodium hydroxide solution (2 mL) at room temperature. Themixture was stirred at the same temperature overnight. The mixture wasneutralized with 1N hydrochloric acid and extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.1005 g). ¹H NMR (300 MHz,CDCl₃) δ1.40-1.55 (2H, m), 1.82-2.01 (4H, m), 2.14-2.25 (1H, m),2.53-2.75 (3H, m), 2.87 (1H, dd, J=16.2, 4.7 Hz), 3.29-3.40 (1H, m),3.65-3.74 (2H, m), 3.87 (3H, s), 4.07-4.25 (4H, m), 4.31-4.42 (2H, m),6.19 (1H, s), 6.55 (1H, s), 7.70 (1H, s), 7.75 (1H, s).

Example 17(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(0.1300 g) which is an optical isomer having shorter retention time andobtained by separating a racemate of ethyl(6-((1-(2-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetateby SFC (column: CHIRALPAK IA (trade name), 20 mm ID×250 mm L,manufactured by Daicel Corporation, mobile phase: carbondioxide/MeOH=860/140), THE (3 mL) and MeOH (3.00 mL) was added 1Naqueous sodium hydroxide solution (2.5 mL) at room temperature. Themixture was stirred at the same temperature overnight. The mixture wasneutralized with 1N hydrochloric acid and extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.1182 g). ¹H NMR (300 MHz,CDCl₃) δ1.38-1.56 (2H, m), 1.81-2.02 (4H, m), 2.14-2.26 (1H, m),2.53-2.75 (3H, m), 2.88 (1H, dd, J=16.2, 4.7 Hz), 3.29-3.40 (1H, m),3.65-3.74 (2H, m), 3.87 (3H, s), 4.07-4.25 (4H, m), 4.31-4.42 (2H, m),6.19 (1H, s), 6.55 (1H, s), 7.71 (1H, s), 7.75 (1H, s).

Example 18(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(0.0716 g) which is an optical isomer having shorter retention time andobtained by separating a racemate of ethyl(6-((1-(5-methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetateby SFC (column: CHIRALCEL OJH (trade name), 20 mm ID×250 mm L,manufactured by Daicel Corporation, mobile phase: carbondioxide/MeOH=880/120), THF (2.5 mL) and MeOH (2.500 mL) was added 1Naqueous sodium hydroxide solution (1.5 mL) at room temperature. Themixture was stirred at the same temperature overnight. The mixture wasneutralized with 1N hydrochloric acid and extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was suspended in a mixed solvent of IPE and hexane. Theprecipitate was collected by filtration, washed with a mixed solvent ofIPE and hexane and dried under reduced pressure to give the titlecompound (0.0597 g).

Example 28(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(56.2 mg) which is an optical isomer having shorter retention time andobtained by separating a racemate of ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetateby HPLC (column: CHIRALPAK IC (trade name), 50 mm ID×500 mm L,manufactured by Daicel Corporation, mobile phase:hexane/2-propanol=600/400), THE (2 mL) and MeOH (1.000 mL) was added 1Naqueous sodium hydroxide solution (2 mL) at room temperature. Themixture was stirred at 60° C. for 20 min. The mixture was neutralizedwith 1N hydrochloric acid and extracted with ethyl acetate. The organiclayer was separated, washed with water and saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was crystallized from ethyl acetate/hexane to give thetitle compound (43 mg). ¹H NMR (400 MHz, DMSO-d₆) δ1.32-1.49 (2H, m),1.53-1.68 (4H, m), 1.82 (4H, d, J=10.4 Hz), 2.00 (1H, d, J=10.8 Hz),2.34-2.46 (2H, m), 2.62 (2H, t, J=11.1 Hz), 2.76 (1H, d, J=15.2 Hz),2.82-2.97 (3H, m), 3.01 (2H, d, J=10.4 Hz), 3.11-3.24 (4H, m), 3.70 (3H,s), 3.95-4.25 (4H, m), 6.53-6.66 (2H, m), 6.70 (1H, s), 7.13 (1H, d,J=7.8 Hz), 7.65 (1H, s), 12.53 (1H, brs).

Example 29(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)aceticacid (Optical Isomer))

To a mixture of ethyl(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetate(61.0 mg) which is an optical isomer having longer retention time andobtained by separating a racemate of ethyl(3-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5-yl)acetateby HPLC (column: CHIRALPAK IC (trade name), 50 mm ID×500 mm L,manufactured by Daicel Corporation, mobile phase:hexane/2-propanol=600/400), THE (2 mL) and MeOH (1.000 mL) was added 1Naqueous sodium hydroxide solution (2 mL) at room temperature. Themixture was stirred at 60° C. for 30 min. The mixture was neutralizedwith 1N hydrochloric acid at room temperature and extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The obtained residue was crystallized from ethylacetate/hexane to give the title compound (44.8 mg).

Example 36(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid

To a mixture of ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(35 mg), THE (1 mL) and MeOH (0.500 mL) was added 1N aqueous sodiumhydroxide solution (1 mL) at room temperature. The mixture was stirredat 60° C. for 30 min. The mixture was neutralized with 1N hydrochloricacid at room temperature and extracted with ethyl acetate. The organiclayer was separated, washed with water and saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was crystallized from ethyl acetate/hexane to give thetitle compound (24.5 mg). ¹H NMR (300 MHz, DMSO-d₆) δ1.32-1.50 (2H, m),1.52-1.70 (4H, m), 1.70-1.93 (4H, m), 1.96-2.13 (1H, m), 2.34-2.48 (2H,m), 2.63 (2H, t, J=11.2 Hz), 2.70-2.97 (4H, m), 3.02 (2H, d, J=11.2 Hz),3.17 (4H, q, J=10.3 Hz), 3.70 (3H, s), 3.99-4.23 (4H, m), 6.56-6.65 (2H,m), 6.70 (1H, s), 7.13 (1H, d, J=9.1 Hz), 7.66 (1H, s), 12.34 (1H, brs).

Example 49

(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (optical isomer) (compound of Example 9) can also be produced bythe following method.

A) ethyl (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer)

A racemate (20.0 g) of ethyl(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate wasseparated by SFC (column: Alcyon SFC CSP Amylose-C (5 μm) 150×4.6 mmI.D., mobile phase: carbon dioxide/ethanol=90/10) to give the titlecompound (9.70 g) having longer retention time.

B) ethyl (6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer)

A mixture of ethyl(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (9.70 g), 10% palladium carbon (2.20 g).and ethyl acetate (240mL) was stirred under a hydrogen atmosphere at normal pressure at roomtemperature for 1 hr. The catalyst was removed by filtration and thefiltrate was concentrated under reduced pressure to give the titlecompound (6.93 g). MS: [M+H]⁺ 238.1.

C) ethyl 1-(5-methoxy-2-nitrophenyl)piperidine-4-carboxylate

To a mixture of 2-fluoro-4-methoxy-1-nitrobenzene (45.9 g), potassiumcarbonate (44.5 g) and DMF (300 mL) was added ethylpiperidine-4-carboxylate (50.6 g) at room temperature. The mixture wasstirred under a nitrogen atmosphere at 60° C. for 1 hr. To the reactionmixture was added water at room temperature, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (83.0 g). MS: [M+H]⁺ 309.1.

D) ethyl 1-(2-amino-5-methoxyphenyl)piperidine-4-carboxylate

A mixture of ethyl 1-(5-methoxy-2-nitrophenyl)piperidine-4-carboxylate(83.0 g), 10% palladium carbon (10.0 g), EtOH (250 mL) and TH (250 mL)was stirred under a hydrogen atmosphere at normal pressure at roomtemperature for 5 hr. The catalyst was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (71.0 g). MS: [M+H]⁺ 279.1.

E) ethyl 1-(2-iodo-5-methoxyphenyl)piperidine-4-carboxylate

To a mixture of ethyl1-(2-amino-5-methoxyphenyl)piperidine-4-carboxylate (71.0 g) andacetonitrile (300 mL) was added 2N hydrochloric acid (400 mL) at 0° C.,and the mixture was stirred at the same temperature for 30 min. To themixture was added a mixture of sodium nitrite (22.9 g) and water (50 mL)at 0° C. and the mixture was stirred under a nitrogen atmosphere at thesame temperature for 30 min. To the mixture was added a mixture ofpotassium iodide (127 g) and water (150 mL) at 0° C., and the mixturewas stirred under a nitrogen atmosphere at 60° C. for 1 hr. To thereaction mixture was added saturated aqueous sodium hydrogen carbonatesolution at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated aqueoussodium thiosulfate solution and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (79.0 g). MS: [M+H]⁺ 390.0.

F) tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of ethyl 1-(2-iodo-5-methoxyphenyl)piperidine-4-carboxylate(12.0 g), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(17.8 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(2.26 g), 2 M aqueous sodium carbonate solution (33.9 mL) and DMF (200mL) was stirred under a nitrogen atmosphere at 100° C. for 2 hr. Thereaction mixture was filtered, water was added to the filtrate at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with water and saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (12.5 g). MS: [M+H]⁺445.3.

G) tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(12.5 g), 10% palladium carbon (5.00 g) and THE (200 mL) was stirredunder a hydrogen atmosphere at normal pressure at room temperature for 5hr. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure to give the title compound (12.4 g).MS: [M+H]⁺ 447.3.

H) ethyl1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidine-4-carboxylate

To a mixture of tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-4-methoxyphenyl)piperidine-1-carboxylate(12.4 g) and ethyl acetate (60 mL) was added 4N hydrogen chloride ethylacetate solution (104 mL) at room temperature. The mixture was stirredunder a nitrogen atmosphere at the same temperature for 40 min, and thereaction mixture was concentrated. To a mixture of the obtained residue,TEA (38.7 mL) and acetonitrile (120 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (14.0 mL) at room temperature. After stirringunder a nitrogen atmosphere at 60° C. for 20 min, the reaction mixturewas concentrated. To the residue was added ethyl acetate, insolublematerial was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (10.9g). MS: [M+H]⁺429.2.

I)(1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol

To a mixture of lithium aluminum hydride (2.68 g) and Et₂O (110 mL) wasadded a solution of ethyl1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidine-4-carboxylate(10.1 g) in Et₂O (45 mL) at 0° C. The mixture was stirred under anitrogen atmosphere at the same temperature for 20 min. To the mixturewere added water and 1N aqueous sodium hydroxide solution, the obtainedprecipitate was removed by filtration, and the filtrate was concentratedunder reduced pressure to give the title compound (8.66 g). MS: [M+H]⁺387.2.

J) ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(Optical Isomer)

To a mixture of(1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol(6.71 g), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (3.43 g) and toluene (70 mL) was added(tributylphosphoranylidene)acetonitrile (6.98 g) at room temperature.The mixture was stirred under a nitrogen atmosphere at 100° C. for 2 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (5.28 g). MS: [M+H]⁺ 606.4.

K)(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(5-methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (9.84 g), THE (200 mL) and MeOH (100 mL) was added 1Naqueous sodium hydroxide solution (195 mL) at room temperature. Themixture was stirred at 60° C. for 1 hr. The reaction mixture wasneutralized with 1N hydrochloric acid at room temperature and extractedwith ethyl acetate. The organic layer was separated, washed with waterand saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained solid was crystallizedfrom ethyl acetate/hexane to give the title compound (8.08 g). ¹H NMR(300 MHz, CDCl₃) δ 1.44-1.64 (2H, m), 1.65-1.74 (3H, m), 1.75-1.95 (4H,m), 2.12-2.26 (1H, m), 2.43-2.74 (6H, m), 2.80-2.90 (1H, m), 2.82-3.14(7H, m), 3.37 (1H, br dd, J=8.5, 5.7 Hz), 3.78 (3H, s), 4.08-4.25 (4H,m), 6.56-6.68 (3H, m), 7.14 (1H, d, J=8.4 Hz), 7.76 (1H, s).

Example 50(6-((1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer) A) ethyl1-(2-(4,4-difluorocyclohex-1-en-1-yl)-5-methoxyphenyl)piperidine-4-carboxylate

A mixture of ethyl 1-(2-iodo-5-methoxyphenyl)piperidine-4-carboxylate(250 mg),2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(270 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(94.0 mg), 2 M aqueous sodium carbonate solution (0.71 mL) and DMF (4mL) was stirred under a nitrogen atmosphere at 100° C. for 2 hr. To thereaction mixture was added water at room temperature, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with water and saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (180 mg). MS: [M+H]⁺ 380.2.

B) ethyl1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidine-4-carboxylate

A mixture of ethyl1-(2-(4,4-difluorocyclohex-1-en-1-yl)-5-methoxyphenyl)piperidine-4-carboxylate(90.0 mg), 10% palladium carbon (30.0 mg) and THE (5 mL) was stirredunder a hydrogen atmosphere at normal pressure at room temperature for 3hr. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure to give the title compound (94.0mg). MS: [M+H]⁺ 382.3.

C)(1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methanol

To a mixture of lithium aluminum hydride (28.1 mg) and Et₂O (3 mL) wasadded a solution of ethyl1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidine-4-carboxylate(94.0 mg) in Et₂O (3 mL) at 0° C. The mixture was stirred under anitrogen atmosphere at 0° C. for 20 min. To the reaction mixture wereadded water and aqueous sodium hydroxide solution, and the obtainedprecipitate was removed by filtration. The filtrate was concentratedunder reduced pressure to give the title compound (80.0 mg). MS: [M+H]⁺340.2.

D) ethyl(6-((1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer)

To a mixture of(1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methanol(80.0 mg), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (50.0 mg) and toluene (3 mL) was added(tributylphosphoranylidene)acetonitrile (102 mg) at room temperature.The mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr.The reaction mixture was concentrated under reduced pressure and theresidue was purified by silica gel-column chromatography (ethylacetate/hexane) to give the title compound (68.0 mg). MS: [M+H]⁺ 559.4.

E)(6-((1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(2-(4,4-difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (68.0 mg), THF (2 mL) and MeOH (1 mL) was added 1Naqueous sodium hydroxide solution (1.46 mL) at room temperature. Themixture was stirred at 60° C. for 2 hr. The reaction mixture wasneutralized with 1N hydrochloric acid at room temperature and extractedwith ethyl acetate. The organic layer was separated, washed with waterand saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained solid was crystallizedfrom ethyl acetate/hexane to give the title compound (54.0 mg). ¹H NMR(300 MHz, DMSO-d₆) δ1.37-1.53 (2H, m), 1.57-1.71 (2H, m), 1.72-1.93 (7H,m), 1.95-2.16 (4H, m), 2.60-2.69 (3H, m), 2.88-3.09 (3H, m), 3.12-3.26(2H, m), 3.70 (3H, s), 4.02-4.19 (4H, m), 6.60-6.71 (3H, m), 7.09 (1H,d, J=8.4 Hz), 7.65 (1H, s).

Example 51(6-((1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer) A) ethyl1-(2-methoxy-5-nitropyridin-4-yl)piperidine-4-carboxylate

A mixture of 4-chloro-2-methoxy-5-nitropyridine (913 mg), ethylpiperidine-4-carboxylate (0.784 mL) and EtOH (15 mL) was stirred at 80°C. overnight. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.50 g). MS: [M+H]⁺ 310.1.

B) ethyl 1-(5-amino-2-methoxypyridin-4-yl)piperidine-4-carboxylate

A mixture of ethyl1-(2-methoxy-5-nitropyridin-4-yl)piperidine-4-carboxylate (1.50 g), 10%palladium carbon (200 mg), EtOH (12 mL) and THF (12 mL) was stirredunder a hydrogen atmosphere at normal pressure at room temperatureovernight. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.24 g). MS: [M+H]⁺ 280.2.

C) ethyl 1-(5-iodo-2-methoxypyridin-4-yl)piperidine-4-carboxylate

To a mixture of ethyl1-(5-amino-2-methoxypyridin-4-yl)piperidine-4-carboxylate (604 mg), 2Nhydrochloric acid (3.5 mL) and acetonitrile (10 mL) was added a mixtureof sodium nitrite (194 mg) and water (2.5 mL) at 0° C., and the mixturewas stirred at the same temperature for 30 min. To the mixture was addeda mixture of potassium iodide (1.08 g) and water (4.5 mL) at 0° C., andthe mixture was stirred at 60° C. for 1 hr. To the reaction mixture wasadded saturated aqueous sodium hydrogen carbonate solution at 0° C., andthe mixture, was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated aqueous sodium thiosulfate solution andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (822mg). MS: [M+H]⁺ 391.1.

D) ethyl1-(5-(4,4-difluorocyclohex-1-en-1-yl)-2-methoxypyridin-4-yl)piperidine-4-carboxylate

A mixture of ethyl1-(5-iodo-2-methoxypyridin-4-yl)piperidine-4-carboxylate (200 mg),2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(150 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(37.5 mg), 2 M aqueous sodium carbonate solution (0.384 mL) and DMF (5mL) was stirred at 100° C. for 5 hr. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (80.1 mg). MS: [M+H]⁺ 381.2.

E) ethyl1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidine-4-carboxylate

A mixture of ethyl1-(5-(4,4-difluorocyclohex-1-en-1-yl)-2-methoxypyridin-4-yl)piperidine-4-carboxylate(80.1 mg), 10% palladium carbon (20.0 mg) and THE (5 mL) was stirredunder a hydrogen atmosphere at normal pressure at room temperatureovernight. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (54.4 mg). MS: [M+H]⁺ 383.2.

F)(1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidin-4-yl)methanol

A mixture of ethyl1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidine-4-carboxylate(54.4 mg), lithium borohydride (17.2 mg) and THE (7 mL) was stirred at60° C. for 3 hr. To the reaction mixture was added saturated aqueousammonium chloride solution at 0° C., and the mixture was extracted withethyl acetate. The organic layer was separated, washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (44.5mg). MS: [M+H]⁺ 341.2.

G) ethyl(6-((1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer)

A mixture of(1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidin-4-yl)methanol(44.5 mg), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (34.1 mg), (tributylphosphoranylidene)acetonitrile (0.171 mL)and toluene (5 mL) was stirred at 100° C. for 6 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (42.6 mg). MS: [M+H]⁺560.3.

H)(6-((1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(5-(4,4-difluorocyclohexyl)-2-methoxypyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (42.6 mg), THE (1.5 mL) and MeOH (1.5 mL) was added 1Naqueous sodium hydroxide solution (0.800 mL) at room temperature. Themixture was stirred at room temperature overnight. The reaction mixturewas neutralized with 1N hydrochloric acid and extracted with ethylacetate. The organic layer was separated, washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound (34.4 mg). ¹H NMR (300 MHz, DMSO-d₆) δ1.21-1.34 (2H, m), 1.37-1.55 (2H, m), 1.58-1.93 (7H, m), 1.97-2.21 (4H,m), 2.57-2.70 (2H, m), 2.71-2.86 (2H, m), 3.03-3.14 (2H, m), 3.16-3.28(2H, m), 3.77 (3H, s), 4.00-4.24 (4H, m), 6.33 (1H, s), 6.70 (1H, s),7.65 (1H, s), 7.90 (1H, s).

Example 52(6-((1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer) A) ethyl6-chloro-4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate

A mixture of ethyl 4,6-dichloronicotinate (5.24 g), 4-piperidylmethanol(4.11 g), N,N-diisopropylethylamine (12.4 mL) and THE (60 mL) wasstirred at room temperature for 2 days. The reaction mixture wasconcentrated under reduced pressure and the residue was diluted withethyl acetate. The obtained mixture was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (6.69g). MS: [M+H]⁺ 299.2.

B) ethyl 6-chloro-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)nicotinate

A mixture of ethyl6-chloro-4-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (6.69 g),chloro(methoxy)methane (5.10 mL), N,N-diisopropylethylamine (15.6 mL)and THE (100 mL) was heated under reflux for 3 hr. The reaction mixturewas concentrated under reduced pressure and the residue was diluted withethyl acetate. The obtained mixture was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (5.62g). MS: [M+H]⁺ 343.2.

C) methyl6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)nicotinate

A mixture of ethyl6-chloro-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)nicotinate (5.62g), sodium methoxide (28% methanol solution, 15.8 g) and methanol (60mL) was heated under reflux for 9 hr. The reaction mixture was dilutedwith ethyl acetate, washed with saturated aqueous ammonium chloridesolution, water and saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (4.43 g). MS: [M+H]⁺ 325.2.

D)(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)methanol

To a mixture of lithium aluminum hydride (0.777 g) and THF (50 mL) wasadded a solution of methyl6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)nicotinate (4.43g) in THE (20 mL) at 0° C., and the mixture was stirred at the sametemperature for 20 min. To the reaction mixture was added sodium sulfate10 hydrate at 0° C., and the mixture was stirred at room temperature for1 hr. The solid was removed by filtration and the filtrate wasconcentrated under reduced pressure to give the title compound (4.16 g).MS: [M+H]⁺ 297.2.

E) 6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)nicotinaldehyde

A mixture of(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)methanol(4.07 g), manganese dioxide (85%, 7.02 g) and toluene (70 mL) wasstirred at 60° C. for 1.5 hr. The solid was removed by filtration andthe filtrate was concentrated under reduced pressure to give the titlecompound (4.12 g). MS: [M+H]⁺ 295.2.

F)2-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)-5-vinylpyridine

To a mixture of methyltriphenylphosphonium iodide (8.24 g) and THF (30mL) was added potassium tert-butoxide (85%, 2.24 g) at 0° C., and themixture was stirred at room temperature for 1 hr. To the mixture wasadded a solution of6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)nicotinaldehyde(2.00 g) in THE (5 mL) at 0° C., and the mixture was stirred at roomtemperature for 30 min. To the reaction mixture was added saturatedaqueous ammonium chloride and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.81g). MS: [M+H]⁺ 293.2.

G)3,3,3-trifluoro-1-(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)propyl2-iodobenzoate

A mixture of2-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)-5-vinylpyridine(1.81 g), 1-trifluoromethyl-1,2-benzoiodoxol-3(1H)-one (containing 60%diatomaceous earth, 5.87 g), tetrakis(acetonitrile)copper(I)hexafluorophosphate (0.461 g) and dichloromethane (40 mL) was stirred atroom temperature overnight. The solid was removed by filtration and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (1.65 g). MS: [M+H]⁺ 609.2.

H)3,3,3-trifluoro-1-(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)propan-1-ol

To a mixture of3,3,3-trifluoro-1-(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)propyl2-iodobenzoate (1.61 g) and ethanol (15 mL) was added 2N aqueous sodiumhydroxide solution (5 mL) at room temperature, and the mixture wasstirred at the same temperature for 3.5 hr. To the reaction mixture wasadded water at room temperature, and the mixture was extracted withethyl acetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.880g). MS: [M+H]⁺ 379.2.

I) S-methyl0-(3,3,3-trifluoro-1-(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)propyl)carbonodithioate

To a mixture of3,3,3-trifluoro-1-(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)propan-1-ol(0.760 g) and THE (20 mL) was added sodium hydride (60% in oil, 0.241 g)at 0° C., and the mixture was stirred at room temperature for 10 min. Tothe mixture was added carbon disulfide (0.604 mL) at 0° C., and themixture was stirred at room temperature for 2 hr. To the mixture wasadded methyl iodide (0.625 mL) at room temperature, and the mixture wasstirred at the same temperature overnight. To the reaction mixture wasadded saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (0.910 g). MS: [M+H]⁺ 469.2.

J)2-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)-5-(3,3,3-trifluoropropyl)pyridine

A mixture of S-methyl0-(3,3,3-trifluoro-1-(6-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)pyridin-3-yl)propyl)carbonodithioate (0.910 g), tributyltin hydride(1.57 mL),azobisisobutyronitrile (0.159 g) and toluene (20 mL) was stirred at 100°C. overnight. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.460 g). MS: [M+H]⁺ 363.2.

K)(1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methanol

A mixture of2-methoxy-4-(4-((methoxymethoxy)methyl)piperidin-1-yl)-5-(3,3,3-trifluoropropyl)pyridine(0.460 g), concentrated hydrochloric acid (1.06 mL) and methanol (10 mL)was stirred at 60° C. for 1.5 hr. To the reaction mixture was addedsaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with water and saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.400 g). MS: [M+H]⁺ 319.2.

L) ethyl(6-((1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer)

A mixture of(1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methanol(0.221 g), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (0.150 g), (tributylphosphoranylidene)acetonitrile (0.332 mL)and toluene (4 mL) was stirred at 100° C. overnight. The reactionmixture was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.230 g). MS: [M+H]⁺ 538.3.

M)(6-((1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(2-methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (0.230 g), THE (2 mL) and ethanol (2 mL) was added 2Naqueous sodium hydroxide solution (1.0 mL) at room temperature, and themixture was stirred at the same temperature for 4 hr. The reactionmixture was concentrated under reduced pressure, diluted with water (15mL) and neutralized with 1N hydrochloric acid (pH 5). The precipitatedsolid was collected by filtration and washed with water to give thetitle compound (0.200 g). ¹H NMR (300 MHz, DMSO-d₆) δ 1.27-1.50 (2H, m),1.67-1.95 (4H, m), 1.98-2.14 (1H, m), 2.52-2.93 (8H, m), 3.17 (3H, br d,J=10.9 Hz), 3.78 (3H, s), 3.99-4.27 (4H, m), 6.34 (1H, s), 6.69 (1H, s),7.65 (1H, s), 7.93 (1H, s), 12.51 (1H, br s).

Reference Example 1

6-(benzyloxy)-2,3-dihydro-4H-pyrano[2,3-c]pyridin-4-one (compound ofExample 1, E)) can also be produced by the following method.

To a mixture of 6-(benzyloxy)-4H-pyrano[2,3-c]pyridin-4-one (45.8 g) andTHE (900 mL) was added dropwise diisobutylaluminum hydride (1.5 Mtoluene solution, 241 mL) at −78° C. over 1 hr. The mixture was stirredat the same temperature for 1 hr. To the reaction mixture was added amixture of silica gel (50 g) and water (50 mL) over 5 hr, and themixture was heated to room temperature and stirred at the sametemperature for 3 hr. The obtained precipitate was removed byfiltration, washed with ethyl acetate, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (23.6g). MS: [M+H]⁺ 256.0.

Reference Example 2

Ethyl (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(compound of Example 1, G)) can also be produced by the followingmethod.

A) 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine

To a mixture of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (3.81 g) andTHF (70 mL) was added n-butyllithium (1.6 M hexane solution, 14.6 mL) at−78° C. The mixture was stirred at the same temperature for 30 min, anda solution of iodine (11.8 g) in THE was added at −78° C. The mixturewas stirred at the same temperature for 1 hr. To the reaction mixturewas added saturated aqueous sodium thiosulfate solution at −78° C., andthe mixture was extracted with ethyl acetate. The organic layer wasseparated, washed with saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (4.40 g). MS: [M+H]⁺ 372.0.

B) 6-(benzyloxy)-4-iodopyridin-3-ol

To a mixture of 2-(benzyloxy)-4-iodo-5-(methoxymethoxy)pyridine (5.48 g)and THF (60 mL) was added 6N hydrochloric acid (40 mL) at roomtemperature. The mixture was stirred at the same temperature for 6 hr.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (4.19g). MS: [M+H]⁺ 328.0.

C) 3-((6-(benzyloxy)-4-iodopyridin-3-yl)oxy)propan-1-ol

A mixture of 6-(benzyloxy)-4-iodopyridin-3-ol (1.37 g), potassiumcarbonate (871 mg), 3-bromo-1-propanol (0.455 mL) and DMF (15 mL) wasstirred at room temperature overnight. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was separated, washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (1.53 g). MS: [M+H]⁺ 386.0.

D) ethyl (2E)-5-((6-(benzyloxy)-4-iodopyridin-3-yl)oxy)pent-2-enoate

A mixture of 3-((6-(benzyloxy)-4-iodopyridin-3-yl)oxy)propan-1-ol (1.28g), ethyl (triphenylphosphoranylidene)acetate (1.39 g), manganesedioxide (2.88 g) and 1,2-dichloroethane (30 mL) was stirred at 90° C.overnight. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.10g). MS: [M+H]⁺ 454.2.

E) ethyl (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate

To a mixture of ethyl(2E)-5-((6-(benzyloxy)-4-iodopyridin-3-yl)oxy)pent-2-enoate (1.10 g),N,N-diisopropylethylamine (0.508 mL), tris(trimethylsilyl)silane (1.50mL) and benzotrifluoride (15 mL) was added azobisisobutyronitrile (120mg) at room temperature. The mixture was stirred at 80° C. for 2 hr. Tothe reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was separated, washed with saturated brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (754 mg). MS: [M+H]⁺ 328.3.

Reference Example 3

Ethyl (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (compound of Example 49, A)) can also be produced bythe following method.

A) (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid

To a mixture of ethyl(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (5.00g), EtOH (25 mL) and THF (25 mL) was added 2N aqueous sodium hydroxidesolution (19.1 mL) at room temperature. The mixture was stirred at thesame temperature overnight and concentrated under reduced pressure. Theresidue was neutralized (pH 6) with 2N hydrochloric acid at 0° C., andthe obtained solid was collected by filtration and washed with water togive the title compound (4.56 g). MS: [M+H]⁺ 300.2.

B) (1S)-1-(1-naphthyl)ethanaminium(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer)

To a mixture of a racemate (1.00 g) of(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid andEtOH (15 mL) was added (1S)-1-(1-naphthyl)ethanamine (572 mg) at roomtemperature. The mixture was gradually heated to 70° C. and water (1.1mL) was added. The mixture was gradually cooled to room temperature andstirred overnight. The mixture was stirred at 0° C. for 1 hr, and theprecipitate was collected by filtration and washed with EtOH and ethylacetate to give the title compound (700 mg, d.r.=94.8:5.2). A mixture ofthe obtained solid, EtOH (12 mL) and water (0.7 mL) was dissolved at70-75° C., the solution was gradually cooled to room temperature andstirred overnight. The mixture was stirred at 0° C. for 2 hr, and theprecipitate was collected by filtration and washed with ethyl acetateand EtOH to give the title compound (559 mg, d.r.=99.6:0.4).

The diastereomer ratio was analyzed by chiral HPLC (CHIRALPAK IC (tradename), 4.6 mm ID×250 mm L, manufactured by Daicel Corporation, mobilephase: 0.1% TFA containing hexane/0.1% TFA containing 2-propanol=80/20).MS: [M+H]⁺ 300.0.

C) (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid(Optical Isomer)

To a mixture of (1S)-1-(1-naphthyl)ethanaminium(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (322 mg) and water (10 mL) was added 2N aqueous sodium hydroxidesolution (5 mL). The reaction mixture was washed with diethyl ether. Theaqueous layer was neutralized with 2N hydrochloric acid (pH 6-7), themixture was stirred at 0° C. for 30 min, and the precipitate wascollected by filtration and washed with water to give the title compound(191 mg). MS: [M+H]⁺ 300.2.

D) ethyl (6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer)

To a mixture of(6-(benzyloxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid(Optical Isomer) (300 mg) and EtOH (12 mL) was added concentratedsulfuric acid (0.2 mL). The mixture was heated under reflux for 7 hr. Tothe reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at room temperature, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure to give the title compound (316 mg). MS: [M+H]⁺328.2.

The Example compounds are shown in the following Tables. In the Tables,MS shows Found. The compounds of Examples 12-16, 19-27, 30-35, 37-48 and53-59 in the following Tables were produced according to the methodsshown in the above-mentioned Examples or methods analogous thereto.

TABLE 1-1 Ex. No. IUPAC name structural formula salt MS 1(6-((1-(5-methoxy-2-(3,3,3- trifluoropropyl)phenyl--piperidin-4-yl)methoxy)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid

509.3 2 (6-((1-(2-methoxy-5- (2,2,3,3,3- pentafluoropropoxy)pyridin-4-yl)piperidin-4- yl)methoxy)-3,4-dihydro-2H- pyrazo[2,3-c]pyridin-4-yl)acetic acid

562.1 3 (3-((1-(2-methoxy-5- (2,2,3,3,3- pentafluoropropoxy)pyridin-4-yl)piperidin-4- yl)methoxy)-6,7-dihydro-5H- cyclopenta[c]pyridin-5-yl)acetic acid

546.1 4 (3-((1-(5-methoxy-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

562.2 5 (6-((1-(2-methoxy-5-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin- 4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

579.4

TABLE 1-2 Ex. No. IUPAC name structural formula salt MS 6(6-((1-(2-methoxy-5-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

579.2 7 (6-((1-(2-methoxy-5-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)pyridin-4-yl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

579.2 8 (6-((1-(5-methoxy-2-(3,3,3- trifluoropropyl)phenyl)-piperidin-4-yl)methoxy)-3,4- dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

509.2 9 (6-((1-(5-methoxy-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

578.2 10 (3-((1-(5-methoxy-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid (optical isomer)

562.2

TABLE 1-3 Ex. No. IUPAC name structural formula salt MS 11(6-((1-(2-methoxy-5- (2,2,3,3,3-pentafluoro- propoxy)pyridin-4-yl)piperidin-4-yl)methoxy)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

562.1 12 (6-((1-(4-methoxy-4′- (morpholin-4-yl)biphenyl-2-yl)piperidin-4-yl)methoxy)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid

574.3 13 (6-((1-(4-methoxy-4′- (trifluoromethoxy)biphenyl-2-yl)piperidin-4- yl)methoxy)-3,4-dihydro-2H- pyrano[2,3-c]pyridin-4-yl)acetic acid

573.2 14 (3-((1-(4-methoxy-4′- (trifluoromethoxy)biphenyl-2-yl)piperidin-4- yl)methoxy)-6,7-dihydro-5H- cyclopenta[c]pyridin-5-yl)acetic acid

557.2 15 (3-((trans-4-(5-methoxy-2- (2-(2,2,2-trifluoroethoxy)pyrimidin-5- yl)phenoxy)cyclohexyl)oxy)- 6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

574.2 16 (6-((trans-4-(5-methoxy-2- (2-(2,2,2-trifluoroethoxy)pyrimidin-5- yl)phenoxy)cyclohexyl)oxy)-3,4-dihydro-2H-pyrano[2,3- c]pyridin-4-yl)acetic acid

590.2

TABLE 1-4 Ex. No. IUPAC name structural formula salt MS 17(6-((1-(2-methoxy-5- (2,2,3,3,3- pentafluoropropoxy)pyridin-4-yl)piperidin-4- yl)methoxy)-3,4-dihydro-2H- pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

562.1 18 (6-((1-(5-methoxy-2-(3,3,3- trifluoropropoxy)phenyl)-piperidin-4-yl)methoxy)-3,4- dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

509.2 19 (3-((trans-4-(5-methoxy-2- (1-(2,2,3,3,3-pentafluoropropyl)piperidin- 4-yl)phenoxy)cyclohexyl)-oxy)-6,7-dihydro-5H- cyclopenta[c]pyridin-5- yl)acetic acid

613.1 20 (3-((trans-4-(5-methoxy-2- (1-(2,2,2-trifluoroethyl)piperidin-4- yl)phenoxy)cyclohexyl)oxy)- 6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

563.2 21 (6-((trans-4-(5-methoxy-2- (1-(2,2,3,3,3-pentafluoropropyl)piperidin- 4-yl)phenoxy)cyclohexyl)-oxy)-3,4-dihydro-2H- pyrano[2,3-c]pyridin-4- yl)acetic acid

629.2

TABLE 1-5 Ex. No. IUPAC name structural formula salt MS 22(6-((trans-4-(5-methoxy-2- (1-(2,2,2- trifluoroethyl)piperidin-4-yl)phenoxy)cyclohexyl)oxy)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid

579.2 23 (6-((1-(5-methoxy-2-(5- (trifluoromethyl)pyridin-2-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

558.1 24 (3-((1-(5-methoxy-2-(5- (trifluoromethyl)pyridin-2-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

542.2 25 (6-((1-(5-methoxy-2-(6- (trifluoromethyl)pyridin-3-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

558.1 26 (3-((1-(5-methoxy-2-(6- (trifluoromethyl)pyridin-3-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

542.2 27 (6-((1-(5-methoxy-2-(1,1,1- trifluoropropan-2-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

509.2

TABLE 1-6 Ex. No. IUPAC name structural formula salt MS 28(6-((1-(5-methoxy-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

578.2 29 (3-((1-(5-methoxy-2-(1- (2,2,2,-trifluoroethyl)-piperidin-4-yl)phenyl)- piperidin-4-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]- pyridin-5-yl)acetic acid (optical isomer))

562.4 30 (3-((1-(5-methoxy-2-(3,3,3- trifluoropropyl)phenyl)-piperidin-4-yl)methoxy)-6,7- dihydro-5H- cyclopenta[c]pyridin-5-yl)acetic acid

493.2 31 (3-((1-(5-methoxy-2-(1,1,1- trifluoropropan-2-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

493.2 32 (3-((1-(5-methoxy-2-(1,1,1- trifluoropropan-2-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

493.2 33 (6-((1-(5-methoxy-2-(4,4,4- trifluorobutyl)phenyl)-piperidin-4-yl)methoxy)-3,4- dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid

523.2

TABLE 1-7 Ex. No. IUPAC name structural formula salt MS 34(3-((1-(5-methoxy-2-(4,4,4- trifluorobutyl)phenyl)-piperidin-4-yl)methoxy)-6,7- dihydro-5H- cyclopenta[c]pyridin-5-yl)acetic acid

507.2 35 (3-((1-(5-methoxy-2-(1,1,1- trifluoropropan-2-yl)phenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

493.2 36 (6-((1-(5-methoxy-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

578.2 37 (6-((1-(5-methoxy-2-(1- (2,2,3,3,3-pentafluoropropyl)piperidin- 4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H- pyrano[2,3-c]pyridin-4- yl)acetic acid

628.2 38 (3-((1-(5-methoxy-2-(1- (2,2,3,3,3-pentafluoropropyl)piperidin- 4-yl)phenyl)piperidin-4-yl)methoxy)-6,7-dihydro-5H- cyclopenta[c]pyridin-5- yl)acetic acid

612.2 39 (6-((1-(2-((2,2- dimethylpropyl)(6- methylpyridin-2-yl)carbamoyl)-5- methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

617.2

TABLE 1-8 Ex. No. IUPAC name structural formula salt MS 40(6-((1-(2-((2,2- dimethylpropyl)(6- methylpyridin-2- yl)carbamoyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]ypridin-4- yl)acetic acid (optical isomer)

617.2 41 (3-((1-(2-((2,2- dimethylpropyl)(4,6- dimethylpyrimidin-2-yl)carbamoyl)-5- methoxyphenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

616.3 42 (3-((1-(2-((2,2- dimethylpropyl)(6- methylpyridin-2-yl)carbamoyl)-5- methoxyphenyl)piperidin-4- yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-5- yl)acetic acid

601.2 43 (6-((1-(2-((2,2- dimethylpropyl)(6- methylpyridin-2-yl)carbamoyl)-5- methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

617.3 44 (6-((1-(2-((2,2- dimethylpropyl)(4,6- dimethylpyrimidin-2-yl)carbamoyl)-5- methoxyphenyl)piperidin-4- yl)methoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid

615.3

TABLE 1-9 Ex. No. IUPAC name structural formula salt MS 45(6-((1-(2-((2,2- dimethylpropyl)(6- methylpyridin-2- yl)carbamoyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)-2,3-dihydro-1H- inden-1-yl)aceticacid

600.2 46 (6-((1-(2-((2,2- dimethylpropyl)(pyridin-2- yl)carbamoyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-chromen-4-yl)acetic acid

602.3 47 (6-((1-(2-(4,4- dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)-1-methyl-2,3- dihydro-1H-inden-1-yl)acetic acid

508.4 48 (6-((1-(2-(4,4- dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)-2,3-dihydro-1H- inden-1-yl)acetic acid

494.3

TABLE 1-10 Ex. No. IUPAC name structural fomrula salt MS 49(6-((1-(5-methoxy-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

578.3 50 (6-((1-(2-(4,4- diflurocyclohexyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

531.3 51 (6-((1-(5-(4,4- difluorocyclohexyl)-2- methoxypyridin-4-yl)piperidin-4- yl)methoxy)-3,4-dihydro- 2H-pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

532.4 52 (6-((1-(2-methoxy-5- (3,3,3- trifluoropropyl)pyridin-4-yl)piperidin-4- yl)methoxy)-3,4-dihydro- 2H-pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

510.3 53 (6-((1-(5-methyl-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

562.3 54 (6-((1-(5-methoxy-2-(4- methoxy-1-(2,2,2-trifluoroethyl)piperidin- 4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro- 2H-pyrano[2,3-c]pyridin-4- yl)acetic acid(optical isomer)

608.4

TABLE 1-11 Ex. No. IUPAC name structural formula salt MS 55(6-((1-(2-methoxy-5-(4,4,4- trifluorobutyl)pyridin-4-yl)piperidin-4-yl)methoxy)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetic acid (optical isomer)

524.3 56 (6-((1-(5-ethyl-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

576.3 57 (6-((1-(5-chloro-2-(1- (2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

582.4 58 (6-((1-(2-(2,2- dimethyltetrahydro-2H- pyran-4-yl)-5-methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid

525.3 59 (6-((1-(5-methoxy-2- ((3,3,4,4- tetrafluoropyrrolidin-1-yl)methyl)phenyl)piperidin- 4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

568.3

Reference Example 4(6-((l-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer) A) ethyl1-(2-fluoro-3-methoxy-6-nitrophenyl)piperidine-4-carboxylate

To a mixture of 2,3-difluoro-1-methoxy-4-nitrobenzene (4.92 g),potassium carbonate (3.09 g) and DMF (30 mL) was added ethylpiperidine-4-carboxylate (4.91 g), and the mixture was stirred under anitrogen atmosphere at 60° C. for 1 hr. To the reaction mixture wasadded water at room temperature, and the mixture was extracted withethyl acetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (8.48g). MS: [M+H]⁺ 327.2.

B) ethyl 1-(6-amino-2-fluoro-3-methoxyphenyl)piperidine-4-carboxylate

A mixture of ethyl1-(2-fluoro-3-methoxy-6-nitrophenyl)piperidine-4-carboxylate (2.00 g),10% palladium carbon (240 mg), THF (10 mL) and EtOH (10 mL) was stirredunder a hydrogen atmosphere at normal pressure at room temperature for 4hr. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.72 g). MS: [M+H]⁺ 297.2.

C) ethyl 1-(2-fluoro-6-iodo-3-methoxyphenyl)piperidine-4-carboxylate

To a mixture of ethyl1-(6-amino-2-fluoro-3-methoxyphenyl)piperidine-4-carboxylate (1.72 g)and acetonitrile (10 mL) was added 2N hydrochloric acid (9.1 mL) at 0°C., and the mixture was stirred at the same temperature for 30 min. Tothe mixture was added a mixture of sodium nitrite (521 mg) and water (2mL) at 0° C., and the mixture was stirred under a nitrogen atmosphere atthe same temperature for 30 min. To the mixture was added a mixture ofpotassium iodide (2.89 g) and water (4 mL) at 0° C., and the mixture wasstirred under a nitrogen atmosphere at 60° C. for 1 hr. To the reactionmixture was added saturated aqueous sodium hydrogen carbonate solutionat room temperature, and the mixture was extracted with ethyl acetate.The organic layer was separated, washed with saturated aqueous sodiumthiosulfate solution and saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (2.19 g). MS: [M+H]⁺408.0.

D) tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-3-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of ethyl1-(2-fluoro-6-iodo-3-methoxyphenyl)piperidine-4-carboxylate (500 mg),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(759 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(180 mg), 2 M aqueous sodium carbonate solution (1.35 mL) and DMF (10mL) was stirred under a nitrogen atmosphere at 100° C. for 4 hr. To thereaction mixture was added water at room temperature, and the mixturewas extracted with ethyl acetate. The organic layer was separated,washed with water and saturated brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (440 mg). MS: [M+H]⁺ 463.3.

E) tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-3-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(440 mg), 10% palladium carbon (150 mg) and THF (10 mL) was stirredunder a hydrogen atmosphere at normal pressure at room temperature for10 hr. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure to give the title compound (500 mg).MS: [M+H]⁺ 465.3.

F) ethyl1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidine-4-carboxylate

To a mixture of tert-butyl4-(2-(4-(ethoxycarbonyl)piperidin-1-yl)-3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate(500 mg) and ethyl acetate (6 mL) was added 4N hydrogen chloride ethylacetate solution (4 mL) at room temperature. The mixture was stirredunder a nitrogen atmosphere at the same temperature for 40 min, and thereaction mixture was concentrated. To a mixture of the obtained residue,TEA (1.50 mL) and acetonitrile (10 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.773 mL) at room temperature. The mixturewas stirred under a nitrogen atmosphere at 60° C. for 20 min, and thereaction mixture was concentrated under reduced pressure. To the residuewas added ethyl acetate, insoluble material was removed by filtration,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (36.0 mg). MS: [M+H]⁺ 447.2.

G)(1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol

To a mixture of lithium aluminum hydride (92.0 mg) and Et₂O (5 mL) wasadded a solution of ethyl1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidine-4-carboxylate(360 mg) in Et₂O (4 mL) at 0° C. The mixture was stirred at the sametemperature for 20 min. To the mixture were added water and 1N aqueoussodium hydroxide solution, the obtained precipitate was removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (270 mg). MS: [M+H]⁺ 405.3.

H) ethyl(6-((1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(Optical Isomer)

To a mixture of(1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methanol(150 mg), ethyl(6-hydroxy-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate (opticalisomer) (60.0 mg) and toluene (3 mL) was added(tributylphosphoranylidene)acetonitrile (122 mg) at room temperature.The mixture was stirred under a nitrogen atmosphere at 100° C. for 5 hr.The reaction mixture was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (102 mg). MS: [M+H]⁺ 624.3.

I)(6-((1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid (Optical Isomer)

To a mixture of ethyl(6-((1-(2-fluoro-3-methoxy-6-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)acetate(optical isomer) (102 mg), THF (3 mL) and MeOH (1.5 mL) was added 1Naqueous sodium hydroxide solution (2.19 mL) at room temperature. Themixture was stirred at 60° C. for 2 hr. The reaction mixture wasneutralized with 1N hydrochloric acid at room temperature and extractedwith ethyl acetate. The organic layer was separated, washed with waterand saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained solid was crystallizedfrom ethyl acetate/hexane to give the title compound (84 mg). ¹H NMR(300 MHz, DMSO-d₆) δ 1.19-1.40 (2H, m), 1.60 (4H, br s), 1.80 (4H, br d,J=10.5 Hz), 1.99-2.09 (1H, m), 2.37-2.47 (2H, m), 2.76-3.27 (12H, m),3.77 (3H, s), 3.99-4.20 (4H, m), 6.69 (1H, s), 6.87-6.98 (2H, m), 7.66(1H, s), 12.10-12.80 (1H, m).

The Reference Example compounds are shown in the following Tables. Inthe Tables, MS shows Found. The compounds of Reference Examples 5-7 inthe following Tables were produced according to the methods shown in theabove-mentioned Examples or Reference Examples or methods analogousthereto.

TABLE 2 Ref. Ex. No. IUPAC name structural formula salt MS 4(6-((1-(2-fluoro-3-methoxy- 6-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

596.3 5 (6-((1-(3-fluoro-5-methoxy- 2-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H- pyrano[2,3-c]pyridin-4- yl)acetic acid(optical isomer)

596.3 6 (6-((1-(2- ((dicyclopropylmethyl)- sulfonyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4- yl)acetic acid (optical isomer)

571.3 7 (6-((1-(4-fluoro-5-methoxy- 2-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H- pyrano[2,3-c]pyridin-4- yl)acetic acid(optical isomer)

596.3

Experimental Example 1

Evaluation of Human GPR40 Agonist Activity with Increase inIntracellular Ca²⁺ Concentration as an Index

CHO(dhfr−) cells that stably expressed human GPR40 were suspended inMEMα (Wako Pure Chemical Industries, Ltd.) containing 10% dialyzed serum(Thermo Fisher Scientific), 10 mM HEPES (Thermo Fisher Scientific), 100U/mL penicillin, 100 μg/mL streptomycin (Wako Pure Chemical Industries,Ltd.), and plated on a 384 well black/clear cell culture plate at 10,000cells/well. After culture overnight in a CO₂ incubator at 37° C., theculture supernatant was removed, and loading buffer [Ca²⁺ probe attachedto Calcium Kit II-iCellux (DOJINDO) was dissolved in assay buffer (20 mMHEPES, 0.1% fatty acid-free BSA (Wako Pure Chemical Industries, Ltd.),2.5 mM probenecid (DOJINDO)-containing HBSS (Thermo Fisher Scientific))]was added at 30 μL/well. After leaving for 1 hr at room temperatureunder light shielding, assay buffer containing the test compound at afinal concentration of 1 μM was added at 10 μL/well in fluorescenceplate reader FLIPR Tetra (Molecular Devices), and the fluorescenceamount was successively measured. Human GPR40 agonist activity wascalculated using an increase in the intracellular Ca²⁺ concentration asan index, wherein the activity of 10 μM of the compound of WO2015/020184 (Example 153:3-cyclopropyl-3-(2-((1-(2-((2-fluoro-2-methylpropyl)(4-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoicacid) was 100%, and the activity when DMSO was added instead of the testcompound was 0%. The results are shown in Table 3.

TABLE 3 Ex. No. activity 1 107% 2 108% 3 109% 4 108% 5 111% 6  59% 7107% 8 103% 9 104% 10 105% 11 107% 17  58% 18  41% 28  54% 29  65% 36110%

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) finely divided powder cellulose 10 mg3) lactose 19 mg 4) magnesium stearate 1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablets)

1) compound of Example 1 33 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets total 140 g

The entire amount of 1), 2) and 3) and 4) (30 g) is kneaded with water,vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and5) (1 g), and the mixture is punched by a tableting machine, whereby1000 tablets containing 30 mg of the compound of Ex. 1 per tablet areobtained.

INDUSTRIAL APPLICABILITY

The compound of the present invention may have superior GPR40 agonistactivity and GLP-1 secretagogue action, and may be useful as an agentfor the prophylaxis or treatment of diabetes and the like.

This application is based on a patent application No. 2017-072813 filedin Japan, the contents of which are incorporated in full herein.

1-15. (canceled)
 16. A compound represented by the formula (I):

wherein X is an oxygen atom or a bond; Y¹ and Y² are each independentlyCH or N; Z is an optionally substituted alkyl group, an optionallysubstituted alkoxy group or a halogen atom; W is an optionallysubstituted alkyl group, an optionally substituted alkoxy group,—NR^(W1)R^(W2), an optionally substituted carbamoyl group or anoptionally substituted cyclic group; R^(W1) is an optionally substitutedalkyl group or an acyl group; R^(W2) is a hydrogen atom or asubstituent; L is

and R¹, R² and R³ are each independently a hydrogen atom or asubstituent; or R¹ and R² are optionally bonded to each other to form,together with each adjacent carbon atom, an optionally furthersubstituted 3- to 6-membered ring, or a salt thereof.
 17. The compoundaccording to claim 16, wherein Z is a C₁₋₆ alkoxy group; W is (1) aC₁₋₁₀ alkyl group optionally substituted by 1 to 5 halogen atoms, (2) aC₁₋₁₀ alkoxy group optionally substituted by 1 to 5 halogen atoms, (3) aC₆₋₁₄ aryl group optionally substituted by 1 to 5 substituents selectedfrom (a) a C₁₋₆ alkoxy group optionally substituted by 1 to 5 halogenatoms, and (b) a 3- to 14-membered non-aromatic heterocyclic group, (4)a 5- to 14-membered aromatic heterocyclic group optionally substitutedby 1 to 5 substituents selected from (a) a C₁₋₆ alkyl group optionallysubstituted by 1 to 5 halogen atoms, and (b) a C₁₋₆ alkoxy groupoptionally substituted by 1 to 5 halogen atoms, (5) a 3- to 14-memberednon-aromatic heterocyclic group optionally substituted by 1 to 5substituents selected from C₁₋₆ alkyl groups optionally substituted by 1to 5 halogen atoms, (6) a carbamoyl group optionally mono- ordi-substituted by substituent(s) selected from (a) a C₁₋₆ alkyl group,and (b) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 5 C₁₋₆ alkyl groups, or (7) a C₃₋₁₀ cycloalkyl groupoptionally substituted by 1 to 5 halogen atoms; R¹ is a hydrogen atom ora C₁₋₆ alkyl group, and R² and R³ are each a hydrogen atom; or a saltthereof.
 18. The compound according to claim 16, wherein X is an oxygenatom or a bond; Y¹ is CH or N; Y² is N; Z is a C₁₋₆ alkoxy group; W is(1) a C₁₋₆ alkyl group optionally substituted by 1 to 5 halogen atoms,(2) a C₁₋₆ alkoxy group optionally substituted by 1 to 5 halogen atoms,(3) a 3- to 14-membered non-aromatic heterocyclic group optionallysubstituted by 1 to 5 substituents selected from C₁₋₆ alkyl groupsoptionally substituted by 1 to 5 halogen atoms, (4) a carbamoyl groupoptionally mono- or di-substituted by substituent(s) selected from (a) aC₁₋₆ alkyl group, and (b) a 5- to 14-membered aromatic heterocyclicgroup optionally substituted by 1 to 5 C₁₋₆ alkyl groups, or (5) a C₃₋₁₀cycloalkyl group optionally substituted by 1 to 5 halogen atoms; L is

and R¹, R² and R³ are each a hydrogen atom; or a salt thereof.
 19. Thecompound according to claim 16, wherein X is an oxygen atom or a bond;Y¹ is CH or N; Y² is N; Z is a C₁₋₆ alkoxy group; W is (1) a C₁₋₆ alkylgroup optionally substituted by 1 to 5 halogen atoms, (2) a 3- to14-membered nonaromatic heterocyclic group optionally substituted by 1to 5 substituents selected from C₁₋₆ alkyl groups optionally substitutedby 1 to 5 halogen atoms, (3) a carbamoyl group optionally mono- ordi-substituted by substituent(s) selected from (a) a C₁₋₆ alkyl group,and (b) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 5 C₁₋₆ alkyl groups, or (4) a C₃₋₁₀ cycloalkyl groupoptionally substituted by 1 to 5 halogen atoms; L is

and R¹, R² and R³ are each a hydrogen atom; or a salt thereof.
 20. Thecompound according to claim 16, which is selected from the groupconsisting of(6-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof,(6-((1-(5-Methoxy-2-(3,3,3-trifluoropropyl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof,(6-((1-(2-Methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof,(6-((1-(5-Methoxy-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof,(6-((1-(2-(4,4-Difluorocyclohexyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof, and(6-((1-(2-Methoxy-5-(3,3,3-trifluoropropyl)pyridin-4-yl)piperidin-4-yl)methoxy)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)aceticacid or a salt thereof.
 21. A medicament comprising the compoundaccording to claim 16 or a salt thereof.
 22. The medicament according toclaim 21, which is a GPR40 receptor function regulator.
 23. Themedicament according to claim 21, which is a prophylactic or therapeuticagent for diabetes.
 24. A method for regulating GPR40 receptor functionin a mammal, comprising administering an effective amount of thecompound according to claim 16 or a salt thereof to the mammal.
 25. Amethod for regulating GPR40 receptor function in a mammal, which is forpreventing or treating obesity or diabetes in a mammal, comprisingadministering an effective amount of the compound according to claim 16or a salt thereof to the mammal.